NHS REC Form
Reference:
14/SC/0157
IRAS Version 3.5
Welcome to the Integrated Research Application System
IRAS Project Filter
The integrated dataset required for your project will be created from the answers you give to the following questions. The system will generate only those questions and sections which (a) apply to your study type and (b) are required by the bodies reviewing your study. Please ensure you answer all the questions before proceeding with your applications. Please enter a short title for this project (maximum 70 characters) PARAMEDIC 2: The Adrenaline Trial 1. Is your project research? Yes
No
2. Select one category from the list below: Clinical trial of an investigational medicinal product
Clinical investigation or other study of a medical device
Combined trial of an investigational medicinal product and an investigational medical device
Other clinical trial to study a novel intervention or randomised clinical trial to compare interventions in clinical practice
Basic science study involving procedures with human participants
Study administering questionnaires/interviews for quantitative analysis, or using mixed quantitative/qualitative methodology
Study involving qualitative methods only
Study limited to working with human tissue samples (or other human biological samples) and data (specific project only)
Study limited to working with data (specific project only)
Research tissue bank
Research database
If your work does not fit any of these categories, select the option below: Other study
2a. Is this a commercially sponsored Phase 1 or Phase 1/2a trial involving healthy volunteers? Yes No
2b. Will the study involve the use of any medical device without a CE Mark, or a CE marked device which has been modified or will be used outside its intended purposes? Yes No
2c. Please answer the following question: Is this trial subject to advice from the Expert Advisory Group on Clinical Trials and the Commission on Human Medicine prior to authorisation from MHRA? Yes No
Yes No
2d. Please answer the following question: Is this a trial of a gene therapy medicinal product? Date: 07/03/2014
2e. Please answer the following question(s): 1
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Commission on Human Medicine prior to authorisation from MHRA? NHS
REC Form
2d. Please answer the following question: Reference:
14/SC/0157
Is this a trial of a gene therapy medicinal product? IRAS Version 3.5
Yes No
2e. Please answer the following question(s): a) Does the study involve the use of any ionising radiation? Yes No
b) Will you be taking new human tissue samples (or other human biological samples)? Yes No
c) Will you be using existing human tissue samples (or other human biological samples)?
Yes No
3. In which countries of the UK will the research sites be located?(Tick all that apply) England Scotland Wales Northern Ireland 3a. In which country of the UK will the lead NHS R&D office be located: England
Scotland
Wales
Northern Ireland
This study does not involve the NHS
4. Which review bodies are you applying to? NHS/HSC Research and Development offices
Social Care Research Ethics Committee
Research Ethics Committee
Medicines and Healthcare products Regulatory Agency (MHRA) – Medicines
Gene Therapy Advisory Committee (GTAC)
National Information Governance Board for Health and Social Care (NIGB)
National Offender Management Service (NOMS) (Prisons & Probation)
For NHS/HSC R&D offices, the CI must create Site­Specific Information Forms for each site, in addition to the study­wide forms, and transfer them to the PIs or local collaborators. 4a. Will you be seeking data from Hospital Episode Statistics (HES) or the Secondary Uses Service (SUS)? Yes No
4b. Will you only be seeking non­identifiable HES/SUS data? Yes No
5. Will any research sites in this study be NHS organisations? Yes No
5a. Are all the research costs and infrastructure costs for this study provided by an NIHR Biomedical Research Centre, NIHR Biomedical Research Unit, NIHR Collaboration for Leadership in Health Research and Care (CLAHRC) or NIHR Research Centre for Patient Safety & Service Quality in all study sites? Yes No
If yes, NHS permission for your study will be processed through the NIHR Coordinated System for gaining NHS Permission Date:
07/03/2014
(NIHR CSP). 2
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5b. Do you wish to make an application for the study to be considered for NIHR Clinical Research Network (CRN) support NIHR Biomedical Research Unit, NIHR Collaboration for Leadership in Health Research and Care (CLAHRC) or NIHR Research Centre for Patient Safety & Service Quality in all study sites? NHS REC Form
Yes No
Reference:
14/SC/0157
IRAS Version 3.5
If yes, NHS permission for your study will be processed through the NIHR Coordinated System for gaining NHS Permission (NIHR CSP). 5b. Do you wish to make an application for the study to be considered for NIHR Clinical Research Network (CRN) support and inclusion in the NIHR Clinical Research Network (CRN) Portfolio? Please see information button for further details. Yes No
If yes, NHS permission for your study will be processed through the NIHR Coordinated System for gaining NHS Permission (NIHR CSP) and you must complete a NIHR Clinical Research Network (CRN) Portfolio Application Form immediately after completing this project filter and before completing and submitting other applications. 6. Do you plan to include any participants who are children?
Yes No
7. Do you plan at any stage of the project to undertake intrusive research involving adults lacking capacity to consent for themselves? Yes No
Answer Yes if you plan to recruit living participants aged 16 or over who lack capacity, or to retain them in the study following loss of capacity. Intrusive research means any research with the living requiring consent in law. This includes use of identifiable tissue samples or personal information, except where application is being made to the NIGB Ethics and Confidentiality Committee to set aside the common law duty of confidentiality in England and Wales. Please consult the guidance notes for further information on the legal frameworks for research involving adults lacking capacity in the UK. 8. Do you plan to include any participants who are prisoners or young offenders in the custody of HM Prison Service or who are offenders supervised by the probation service in England or Wales? Yes No
9. Is the study or any part of it being undertaken as an educational project? Yes No
10. Will this research be financially supported by the United States Department of Health and Human Services or any of its divisions, agencies or programs? Yes No
11. Will identifiable patient data be accessed outside the care team without prior consent at any stage of the project (including identification of potential participants)? Yes No
Integrated Research Application System Application Form for Clinical trial of an investigational medicinal product
Application to NHS/HSC Research Ethics Committee Date: 07/03/2014
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The Chief Investigator should complete this form. Guidance on the questions is available wherever you see this symbol displayed. We recommend reading the guidance first. The complete guidance and a glossary are available by selecting Help. Yes No
NHS
REC Form
Reference:
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IRAS Version 3.5
Integrated Research Application System Application Form for Clinical trial of an investigational medicinal product
Application to NHS/HSC Research Ethics Committee The Chief Investigator should complete this form. Guidance on the questions is available wherever you see this symbol displayed. We recommend reading the guidance first. The complete guidance and a glossary are available by selecting Help. Please define any terms or acronyms that might not be familar to lay reviewers of the application. Short title and version number: (maximum 70 characters ­ this will be inserted as header on all forms) PARAMEDIC 2: The Adrenaline Trial
Please complete these details after you have booked the REC application for review. REC Name: Oxford C REC
REC Reference Number: 14/SC/0157
Submission date: 07/03/2014
PART A: Core study information
1. ADMINISTRATIVE DETAILS A1. Full title of the research: Prehospital Assessment of the Role of Adrenaline: Measuring the Effectiveness of Drug administration In Cardiac arrest A3­2. National coordinating investigator (for a multicentre trial) or principal investigator (for a single centre trial) National coordinating investigator
Principal investigator
Given name
Gavin
Family name
Perkins
Qualification (MD...)
Institution name
University of Warwick
Institution department name Warwick Clinical Trials Unit
Street address
Gibbet Hill Road
Town/city
Coventry
Post Code
CV4 7AL
Country
UNITED KINGDOM
Date:
07/03/2014
Work E­mail
* Personal E­mail
Work Telephone
147538/575440/1/735
Street address
Gibbet Hill Road
NHS
REC Form
Town/city
Reference:
14/SC/0157
Coventry
Post Code
CV4 7AL
Country
UNITED KINGDOM
IRAS Version 3.5
Work E­mail
* Personal E­mail
Work Telephone
* Personal Telephone/Mobile
Fax
* This information is optional. It will not be placed in the public domain or disclosed to any other third party without prior consent. A copy of a current CV (maximum 2 pages of A4) for the Chief Investigator must be submitted with the application. A4. Who is the contact on behalf of the sponsor for all correspondence relating to applications for this project? This contact will receive copies of all correspondence from REC and R&D reviewers that is sent to the CI. Title Forename/Initials Surname
Address
Medical School, Gibbet Hill Road
Coventry
Post Code
CV4 7AL
E­mail
Telephone
Fax
A5­1. Research reference numbers. Please give any relevant references for your study: Applicant's/organisation's own reference number, e.g. R & D (if available): Sponsor's/protocol number: Protocol Version: 1.0
Protocol Date: 07/03/2014
Funder's reference number: 12/127/126
Project website: TBC
Registry reference number(s): The Department of Health’s Research Governance Framework for Health and Social Care and the research governance frameworks for Wales, Scotland and Northern Ireland set out the requirement for registration of trials. Furthermore: Article 19 of the World Medical Association Declaration of Helsinki adopted in 2008 states that "every clinical trial must be registered on a publicly accessible database before recruitment of the first subject"; and the International Committee of Medical Journal Editors (ICMJE) will consider a clinical trial for publication only if it has been registered in an appropriate registry. Please see guidance for more information. International Standard Randomised Controlled Trial Number (ISRCTN): ClinicalTrials.gov Identifier (NCT number): European Clinical Trials Database (EudraCT) number: Additional reference number(s): 2014­000792­11
Ref.Number Description Reference Number A5­2. Is this application linked to a previous study or another current application? Yes No
Please give brief details and reference numbers. Date: 07/03/2014
2. OVERVIEW OF THE RESEARCH 5
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NHS REC Form
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A5­2. Is this application linked to a previous study or another current application? 14/SC/0157
Yes No
Please give brief details and reference numbers. 2. OVERVIEW OF THE RESEARCH To provide all the information required by review bodies and research information systems, we ask a number of specific questions. This section invites you to give an overview using language comprehensible to lay reviewers and members of the public. Please read the guidance notes for advice on this section.
A6­1. Summary of the study. Please provide a brief summary of the research (maximum 300 words) using language easily understood by lay reviewers and members of the public. Where the research is reviewed by a REC within the UK Health Departments Research Ethics Service, this summary will be published on the website of the National Research Ethics Service following the ethical review. A cardiac arrest occurs when the heart suddenly stops beating, and is one of the most severe medical emergencies. Over 50,000 people die each year following an out of hospital cardiac arrest (OHCA) in the UK, less than 10% of patients survive. Although adrenaline has been used to treat cardiac arrest for a number of years, no one is really sure about whether it is safe and effective for improving long­term survival and helping the brain to recover. The aim of this trial is to work out how safe and effective adrenaline is as a treatment for patients who suffer out of hospital cardiac arrest. This trial will involve putting people into two groups where one group receive the active drug (adrenaline) and the other group a dummy drug (known as a placebo). The results are compared to see if one is better. To try to make sure the groups are the same to start with, each patient is put into a group by chance (randomly). The study is referred to as a “double blind trial”, as neither the patient nor the paramedic / nurse/ doctor will know in which treatment group someone was in. We will collect data on 8,000 patients who have been treated for cardiac arrest. All surviving patients will be invited to take part in the follow up which involves completing questionaires about health and quality of life after the cardiac arrest. A6­2. Summary of main issues. Please summarise the main ethical, legal, or management issues arising from your study and say how you have addressed them. Not all studies raise significant issues. Some studies may have straightforward ethical or other issues that can be identified and managed routinely. Others may present significant issues requiring further consideration by a REC, R&D office or other review body (as appropriate to the issue). Studies that present a minimal risk to participants may raise complex organisational or legal issues. You should try to consider all the types of issues that the different reviewers may need to consider. There are a number of important ethical issues to be considered in conducting this trial. 1. The trial involves withholding a drug (adrenaline) that is currently given as part of standard care. Section 1.1 of the protocol summarises the current evidence about the use of adrenaline as a treatment for cardiac arrest. In brief there is some evidence that adrenaline leads to better short­term survival. Whether it improves long­term survival and how it
affects brain function after cardiac arrest is uncertain. Whilst some studies suggest it may be beneficial, others suggest it may be ineffective or harmful. The trial has the support of the Resuscitation Council (UK), Association of Ambulance Medical Directors and College of Paramedics (letters of support enclosed). Our survey of UK clinician’s views about the effectiveness of adrenaline shows substantial uncertainty amongst the clinical community. A placebo controlled trial is necessary to resolve this uncertainty. 2. Patients will be enrolled in the trial prior to consent being obtained. The occurrence of an out of hospital cardiac arrest is unpredictable. Within seconds of cardiac arrest a person becomes unconscious and thus incapacitated. Treatment must be started immediately in an attempt to save the person’s life. Studies suggest that if adrenaline is effective, the earlier it is given the more likely it will be beneficial. In this setting it will not be practical to consult a carer or independent registered medical practitioner without placing the potential participant at risk of harm from delaying emergency treatment. It will not therefore be possible to obtain prospective consent directly from the research participant. We plan to obtain consent from the patient or their legal representative as soon as is practicable once the initial emergency has passed to inform them of their participation and request consent to continue with data collection and follow up. We will ensure that general information about the trial and contact details for further information is freely available in public forums throughout the trial. Systems will be put in place (similar to the established systems for informing ambulance staff about a Do Not Attempt Resuscitation Decision) to allow a patient to decline in advance participation in the trial in the event that they sustain a cardiac arrest 3. Patients and their next of kin will be informed about the trial when they are particularly vulnerable, either because of 6
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their medical condition (patients) or because of extreme distress (relatives). The research team will work closely with the clinical teams caring for the patients to ensure that any approach is made as sensitively as possible and that support is available for patients and families who are distressed. The research paramedics will have training in assessing capacity to consent to research and in speaking to families in emotionally difficult situations. initial emergency has passed to inform them of their participation and request consent to continue with data collection and follow up. We will ensure that general information about the trial and contact details for further information is freely NHS
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available in public forums throughout the trial. Systems will be put in place (similar to the established systems for 14/SC/0157
informing ambulance staff about a Do Not Attempt Resuscitation Decision) to allow a patient to decline in advance participation in the trial in the event that they sustain a cardiac arrest 3. Patients and their next of kin will be informed about the trial when they are particularly vulnerable, either because of their medical condition (patients) or because of extreme distress (relatives). The research team will work closely with the clinical teams caring for the patients to ensure that any approach is made as sensitively as possible and that support is available for patients and families who are distressed. The research paramedics will have training in assessing capacity to consent to research and in speaking to families in emotionally difficult situations. 4. Some participants may lack capacity to consent to continue in the study. The Research Paramedic or hospital team will assess if the patient has capacity to consent. In the event that a patient lacks capacity to consent, the Research Paramedic will work with the hospital team to identify a legal representative. 5. The patient may regain capacity as the study progresses. It is possible that the patient will have regained capacity by the time the 3 month visit is due. When contacting the legal representative to arrange the 3 month visit, we will ask to speak to the patient. If on assessment of the patient either on the phone or on the visit it is found that the patient still lacks capacity the legal representative will be asked to complete the questionnaires on behalf of the patient. If the patient has capacity then information will be provided about the trial and consent sought. Specific guidelines have been
written by the trial team if the scenario arises that a legal representative responds on behalf of the patient to an invitation letter by post and wants to take part with postal questionnaires only (i.e capacity cannot be established face to
face). 6. The need to inform next of kin of participants who do not survive about the trial. Informing the family about the trial ensures that the process of trial recruitment is open and transparent, and reduces the likelihood that family members discover at a later date that their relative was involved in a trial without their knowledge. However, knowledge of trial participation after the event may also place a significant burden on the next of kin at a time of heightened emotional distress due to the loss of their relative or friend. Any strategy to inform family or next of kin following a patient’s death needs to carefully balance the need for transparency with the need to minimise their distress. There are a number of ways in which we could approach informing the relatives of those that do not survive. a) Passive methods include placing information about the trial in publically accessible places and targeted sites likely to be attended by relatives of the deceased (e.g. in the ambulance, hospitals, GP surgeries, Registrar of Births and Deaths offices). Such information would contain brief details about the study and a contact telephone number and address for further information. An advantage of passive methods is that they allow people to make a choice about whether they wish to seek further information and the timing of that approach. However one cannot be certain that relatives of all participants will see them. Discussion with investigators of previous UK trials (e.g. CRASH trials, Brain injury trials) indicates that passive strategies, although not formally evaluated, have been used successfully. b) Active strategies involve making direct contact with relatives (e.g. posting or hand­delivering a participant information leaflet, organising for a face to face meeting or telephone call). Concerns about the potential burdens to information recipients and the practicalities of this approach mean that it has not been used in previous UK out of hospital cardiac arrest trials. There are practical barriers to providing information actively. The sudden and unpredicted nature of cardiac arrest mean that the relatives / next of kin may not be identifiable at the time of the cardiac arrest. For people where resuscitation efforts are terminated in the home (approximately 40% of total cases) it is not possible for the paramedic who attends the cardiac arrest to spend the necessary time to explain about the study and answer questions. Given these difficulties with face­to­face consultation an alternative is to send written information by post. We have concerns that this un­solicited approach and absence of an opportunity to ask questions immediately upon receipt could exacerbate an already traumatic and stressful experience. We have carefully considered the benefits and burdens of different approaches to informing the relatives of the deceased about the trial. We have concluded that the passive approach outlined above will minimise distress to relatives while maintaining transparency and openness about participation in the trial. We will monitor how this approach works during the pilot phase of the study and if necessary revise during the progression to the main trial. We have discussed this in detail with our clinical ethicist and patient representatives (comments enclosed) and have their support for this approach. However we would welcome the views of the ethics committee on this difficult question. 3. PURPOSE AND DESIGN OF THE RESEARCH A7. Select the appropriate methodology description for this research. Please tick all that apply: Case series/ case note review
Case control
Cohort observation
Controlled trial without randomisation
Cross­sectional study
Database analysis
Epidemiology
Feasibility/ pilot study
Laboratory study
Date: Metanalysis
07/03/2014
Qualitative research
Questionnaire, interview or observation study
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Database analysis
Epidemiology
NHS REC
Form
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Feasibility/ pilot study
IRAS Version 3.5
Laboratory study
Metanalysis
Qualitative research
Questionnaire, interview or observation study
Randomised controlled trial
Other (please specify)
A8. Type of medicinal trial: Clinical trial of an unlicensed investigational medicinal product
Clinical trial of a licensed medicinal product in new conditions of use (different from those in the SmPC, i.e. new target population, new dosage schemes, new administration route, etc.)
Clinical trial of a licensed medicinal product used according to the SmPC
Other (please specify)
A9. Phase of medicinal trial: (Tick one category only) Human pharmacology (Phase I)
Yes No
Therapeutic exploratory trial (Phase II)
Yes No
Therapeutic confirmatory trial (Phase III)
Yes No
Therapeutic use trial (Phase IV)
Yes No
A10. What is the principal research question/objective? Please put this in language comprehensible to a lay person. To determine the clinical effectiveness of adrenaline in the treatment of out of hospital cardiac arrest, measured as survival to 30 days. A11. What are the secondary research questions/objectives if applicable? Please put this in language comprehensible to a lay person. To evaluate the effects of adrenaline on survival and recovery of survivors at 3, 6 and 12 months after the cardiac arrest,
and to establish the cost­effectiveness of using adrenaline. A12. What is the scientific justification for the research? Please put this in language comprehensible to a lay person. Use of adrenaline in cardiac arrest increases short­term survival (hours) but there remains doubt whether this is translated into increased long­term outcomes (days, months). Observational studies suggest an association between adrenaline and worse long­term survival. Adrenaline is currently used to treat cardiac arrests, and if harmful, may be responsible for many avoidable deaths. Therefore it is crucial to answer the questions about adrenaline as quickly as possible. A randomised controlled trial of adrenaline has the support of key stakeholders such as the College of Paramedics, Ambulance Service Medical Directors, Joint Royal College Ambulance Liaison Committee, Resuscitation Council (UK) and patient representatives. A13. Please summarise your design and methodology. It should be clear exactly what will happen to the research participant, how many times and in what order. Please complete this section in language comprehensible to the lay person. Do not simply reproduce or refer to the protocol. Further guidance is available in the guidance notes. This trial will involve putting people into two groups where one group receive the active drug (in this case adrenaline) and the other group a dummy drug (known as a placebo). The two groups will have the same number of patients (4,000 in each). The results will be compared to see if one is better. To try to make sure the groups are the same to start with, each patient is put into a group by chance (randomly). The study is referred to as a “double blind trial”, as neither the patient nor the paramedic / nurse/ doctor will know which treatment group someone was in. 8
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Whether the patients survive to 30 days and recovery of the patients will be compared in both groups. It is possible to find this data without the patient having to do anything, as long as the patient does not object to us collecting this data from their medical notes and NHS databases. This trial will involve putting people into two groups where one group receive the active drug (in this case adrenaline) and the other group a dummy drug (known as a placebo). The two groups will have the same number of patients NHS
REC Form
Reference:
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(4,000 in each). The results will be compared to see if one is better. To try to make sure the groups are the same to 14/SC/0157
start with, each patient is put into a group by chance (randomly). The study is referred to as a “double blind trial”, as neither the patient nor the paramedic / nurse/ doctor will know which treatment group someone was in. Whether the patients survive to 30 days and recovery of the patients will be compared in both groups. It is possible to find this data without the patient having to do anything, as long as the patient does not object to us collecting this data from their medical notes and NHS databases. All patients who survive the cardiac arrest will be contacted by the Research Paramedic in hospital once they are on the
ward and the initial emergency has passed. The Research Paramedic will explain the trial and that the patient has been included. The Research Paramedic will answer any initial questions and give the patient an information sheet to read. The Research Paramedic will then go back and check with the patient if they are happy for us to continue to collect data and take part in the follow up. If someone does not have the mental capacity to consent we will inform their next of kin known as the personal legal representative and ask them to consent of their behalf. If the patient wants to take part in the follow up this will involve completing questionnaires about their quality of life and general health at 3 months and 6 months after the cardiac arrest. The trial is due to start in September 2014. Data will be monitored regularly and the trial may need to stop if a difference is found. Otherwise data will be collected for 3.5 years and results will be known in 2019. A14­1. In which aspects of the research process have you actively involved, or will you involve, patients, service users, and/or their carers, or members of the public? Design of the research
Management of the research
Undertaking the research
Analysis of results
Dissemination of findings
None of the above
Give details of involvement, or if none please justify the absence of involvement. is our patient public representative, a former senior police officer with extensive experience of working with charities dedicated to reducing death from cardiac arrest. has attended meetings and discussions and has been involved in the production of trial documentation including the protocol, the patient information sheet and consent form. He will attend trial related meetings throughout the trial. We will also include two patient public representatives on the Trial Steering Committee.
A14­2. Have you tested the acceptability of using patient identifiable data in this study without consent? Please give details. The PARAMEDIC Trial and OHCAO studies use identificable data from participants without consent. No complaints or requests for withdrawal of data have been received. 4. RISKS AND ETHICAL ISSUES RESEARCH PARTICIPANTS A17­1. Please list the principal inclusion criteria (list the most important, max 5000 characters). 1.Cardiac arrest in out of hospital environment 2.Advanced life support initiated and / or continued by ambulance service clinician A17­2. Please list the principal exclusion criteria (list the most important, max 5000 characters). 1.Known or apparent pregnancy 2.Known or apparently aged under 16 years 3.Cardiac arrest secondary to anaphylaxis 4.Adrenaline given prior to arrival of ambulance service clinician Date: 07/03/2014
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A17­2. Please list the principal exclusion criteria (list the most important, max 5000 characters). NHS REC Form
Reference:
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1.Known or apparent pregnancy 14/SC/0157
2.Known or apparently aged under 16 years 3.Cardiac arrest secondary to anaphylaxis 4.Adrenaline given prior to arrival of ambulance service clinician RESEARCH PROCEDURES, RISKS AND BENEFITS A18. Give details of all non­clinical intervention(s) or procedure(s) that will be received by participants as part of the research protocol. These include seeking consent, interviews, non­clinical observations and use of questionnaires. Please complete the columns for each intervention/procedure as follows: 1. Total number of interventions/procedures to be received by each participant as part of the research protocol. 2. If this intervention/procedure would be routinely given to participants as part of their care outside the research, how many of the total would be routine? 3. Average time taken per intervention/procedure (minutes, hours or days) 4. Details of who will conduct the intervention/procedure, and where it will take place. Intervention or procedure 1 2 3 4 Questionnaires: SF12 and EQ­5D administered at 3 and 6 months post cardiac arrest 2 0 15 minutes
Paramedic Research Fellow, home
Questionnaires Mini Mental State Examination (MMSE, Hospital Anxiety and Depression Scale (HADS) Post Traumatic Stress (PTSD) at 3 months post cardiac arrest
1 0 15 minutes
Paramedic Research Fellow, home
Modified Rankin Scale (mRS) hospital discharge, 3 and 6 3 0 5 minutes Paramedic Research Fellow and/or months
hospital staff, home Consent patient/ legal representative
1 0 30 minutes
Paramedic Research Fellow, hospital/home
IQCODE and 2 simple questions 3 and 6 months post cardiac arrest
2
Paramedic Research Fellow, home
5min
A19. Give details of any clinical intervention(s) or procedure(s) to be received by participants as part of the research protocol. These include uses of medicinal products or devices, other medical treatments or assessments, mental health interventions, imaging investigations and taking samples of human biological material. Include procedures which might be received as routine clinical care outside of the research. Please complete the columns for each intervention/procedure as follows: 1. Total number of interventions/procedures to be received by each participant as part of the research protocol. 2. If this intervention/procedure would be routinely given to participants as part of their care outside the research, how many of the total would be routine? 3. Average time taken per intervention/procedure (minutes, hours or days). 4. Details of who will conduct the intervention/procedure, and where it will take place. Intervention or procedure 1 2 3 4 Advanced Life Saving Resuscitation
1
1
20minutes
Ambulance Service Staff
A20. Will you withhold an intervention or procedure, which would normally be considered a part of routine care? Yes No
If Yes, please give details, explain the risks and justify the need to withhold the intervention or procedure:
The primary objective of this trial is to determine the clinical effectiveness of adrenaline in the treatment of OHCA. Therefore we are conducting a randomised controlled trial whereby half the patients will recieve adrenaline and half will recieve a comparator i.e placebo. A21. How long do you expect each participant to be in the study in total? 10
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Approximately 6% of the patients (surviving the cardiac arrest) will potentially be in the study for 12 months. The primary objective of this trial is to determine the clinical effectiveness of adrenaline in the treatment of OHCA. Therefore we are conducting a randomised controlled trial whereby half the patients will recieve adrenaline and half NHS
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will recieve a comparator i.e placebo. 14/SC/0157
A21. How long do you expect each participant to be in the study in total? Approximately 6% of the patients (surviving the cardiac arrest) will potentially be in the study for 12 months. A22. What are the potential risks and burdens for research participants and how will you minimise them? For all studies, describe any potential adverse effects, pain, discomfort, distress, intrusion, inconvenience or changes to lifestyle. Only describe risks or burdens that could occur as a result of participation in the research. Say what steps would be taken to minimise risks and burdens as far as possible. Risks and burdens: A fundamental issue in this trial is the question of whether the current evidence on the use of adrenaline in cardiac arrest raises sufficient doubt about its efficacy and concern about its potential harm to justify a trial that involves withholding adrenaline from some participants. Most clinical drug trials involve either the comparison of a new drug with the current best treatment or in cases where no current best treatment exists, with a placebo. This trial is unusual in that the underlying hypothesis is that current best practice may be harmful therefore it is ethically necessary to seek evidence to confirm or refute this hypothesis, and that this evidence can only reliably be obtained by a trial that includes participants who do not receive currently recommended treatment. The aim is not to investigate whether another drug is better than adrenaline but to investigate whether adrenaline is more harmful than no adrenaline. The hypothesis that adrenaline is harmful raises the question of what is meant by harm. As we have outlined in our review of current evidence, there is evidence that adrenaline as currently used improves the rate of return of spontaneous circulation (ROSC). Thus it is possible that some people who are entered into the trial and are randomised to receive placebo may fail to achieve return of spontaneous circulation as a result of participating in the trial. However the available evidence on long­term survival (survival to hospital discharge) suggests that some participants who are randomised to placebo will survive to leave hospital when they would have died if they had received adrenaline; that is they will survive as a result of participating in the trial. So for individual participants there is a risk/benefit trade­off for participation which is uncertain because we cannot know on an individual patient basis which person will benefit from the adrenaline and who will be harmed by it. The current evidence suggests that more people will be harmed than will benefit (if we consider survival to discharge more beneficial than initial survival followed by early death). However the evidence is not so strong that we can say adrenaline should not be used. As we have shown in our survey of practitioners there is equipoise on this question. Given the uncertainty of the evidence, and the life threatening nature of the condition being treated, it is ethically important that we obtain the best evidence we can to justify treatment, while ensuring that the interests of the research
participants remain paramount. In considering the interests of the research participants the question is whether for any individual participant the benefits of participating outweigh the risk of harm, or at least the harm/benefit balance is neutral. Based on current evidence it would seem that risks and benefits from participating in this trial are reasonably balanced (if a participant is randomised to placebo they may have a reduced chance of immediate survival but an increased chance of surviving to leave hospital. Our initial PPI work suggest that members of the public weigh long term survival higher than short term recovery of spontaneous circulation so it would seem reasonable to assume potential participants might agree to taking part if they were able to do so. Minimising risk The study will be overseen by a Trial Steering Committee (TSC) and Data Monitoring Committee (DMC) appointed by the National Institute for Health Research Health Technology Assessment Programme Director. The majority of members of the TSC will be independent from the study investigators. All members of the DMC will be independent. The study Chief Investigators and other members of the study team may attend meetings in an advisory capacity at the request of the DMC chair. The role of the TSC is to provide overall supervision for a trial on behalf of the Trial Sponsor and Trial Funder and to ensure that the trial is conducted to the rigorous standards set out in the Department of Health’s Research Governance Framework for Health and Social Care and the Guidelines for Good Clinical Practice. The Data Monitoring Committee (DMC) will monitor safety in this trial. The outcomes of primary interest are long­term outcomes (30 day survival and neurological status). We will regularly prepare reports for the DMC initially at an interval to be confirmed by that group. The DMC will determine the nature of any early stopping rules. We suggest a differing threshold is adopted for early termination if standard care (adrenaline) is more effective compared to if placebo is more effective. This is based on a combination of minimising any risks to patients whilst producing robust evidence that will change practice. We suggest that the balance of evidence that would be needed to change current standard practice (adrenaline use) to be greater. Patient and public involvement. Because of the particular ethical difficulty of conducting a trial which involves withholding a standard treatment, and the major life changing impact on participants, it will be imperative to have procedures for close surveillance of trial data. To address these concerns we will include two PPI representatives in the Trial Steering Committee. Date:
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A23. Will interviews/ questionnaires or group discussions include topics that might be sensitive, embarrassing or upsetting, or is it possible that criminal or other disclosures requiring action could occur during the study? Patient and public involvement. Because of the particular ethical difficulty of conducting a trial which involves NHS
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procedures for close surveillance of trial data. To address these concerns we will include two PPI representatives in the Trial Steering Committee. A23. Will interviews/ questionnaires or group discussions include topics that might be sensitive, embarrassing or upsetting, or is it possible that criminal or other disclosures requiring action could occur during the study? Yes No
If Yes, please give details of procedures in place to deal with these issues:
Patients and relatives of victims of out of hospital cardiac arrest often suffer from symptoms of anxiety, depression and post traumatic stress disorder for weeks or months after the initial event. Researchers conducting interviews will be trained on how to recognise and sensitively support patients or their relatives who are distressed during the conduct of interviews / questionnaires. The Researchers will be provided with information about systems available to support them at this difficult time (e.g. http://www.bereavementadvice.org/useful­contacts/useful­contacts­ .php) and will facilitate contact with professional healthcare services (e.g. general practitioner) if requested It is not anticipated that criminal or other disclosures requiring action will occur during the study. A24. What is the potential for benefit to research participants? There is the potential amongst patients who receive adrenaline that a greater number will have their hearts re­started and will survive in the short term (mins to hours). The available evidence on long­term survival (survival to hospital discharge) suggests that some participants who are randomised to placebo will survive to leave hospital when they would have died if they had received adrenaline; that is they will survive as a result of participating in the trial. Participants receiving placebo may also avoid the potential side effects of adrenaline (irregular heart beat, adverse effects on metabolics, brain injury). Participation in the study will provide critical information about the most effective way to resuscitate future patients that sustain an out of hospital cardiac arrest. A25. What arrangements are being made for continued provision of the intervention for participants, if appropriate, once the research has finished? May apply to any clinical intervention, including a drug, medical device, mental health intervention, complementary therapy, physiotherapy, dietary manipulation, lifestyle change, etc. Not Applicable. A26. What are the potential risks for the researchers themselves? (if any) Conducting research in cardiac arrest can be emotionally draining to researchers who are faced daily with stories of sad and tragic deaths of many hundreds of people. It is possible that this exposure may lead to some individuals becoming distressed by such exposure. Our working systems promote a culture of openness and we encourage discussion and sharing if researchers feel burdened or troubled by participation the study. The study co­ordinating centre (University of Warwick) and partner Ambulance Trusts have access to trained and experienced councillors who are accessible through our occupational health departments. The availability of these support services are highlighted during the induction of new staff. Access can be via self referral or supported by the individuals line manager. RECRUITMENT AND INFORMED CONSENT In this section we ask you to describe the recruitment procedures for the study. Please give separate details for different study groups where appropriate.
A27­1. How will potential participants, records or samples be identified? Who will carry this out and what resources will be used?For example, identification may involve a disease register, computerised search of GP records, or review of medical records. Indicate whether this will be done by the direct healthcare team or by researchers acting under 12
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arrangements with the responsible care organisation(s). Patients will be enrolled into the trial by the attending paramedic if they meet the eligiblity criteria. Identification of each trial patient will be carried out by the participating amublance services. They will set up their own different study groups where appropriate.
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A27­1. How will potential participants, records or samples be identified? Who will carry this out and what resources will be used?For example, identification may involve a disease register, computerised search of GP records, or review of medical records. Indicate whether this will be done by the direct healthcare team or by researchers acting under arrangements with the responsible care organisation(s). Patients will be enrolled into the trial by the attending paramedic if they meet the eligiblity criteria. Identification of each trial patient will be carried out by the participating amublance services. They will set up their own internal systems for ensuring all trial patients are notified to the trial co­ordinating centre (Warwick Clinical Trials Unit (WCTU) as quickly as possible. A27­2. Will the identification of potential participants involve reviewing or screening the identifiable personal information of patients, service users or any other person? Yes No
Please give details below: A28. Will any participants be recruited by publicity through posters, leaflets, adverts or websites? Yes No
A29. How and by whom will potential participants first be approached? The first attempt to contact the patient and inform them of their enrolment into the trial will be during their stay in hospital before hospital discharge. We plan to make contact as soon as practically possible after the initial emergency has passed and taking the utmost care and sensitivity in doing so. Following our experience from a 4,400 patient study
in out of hospital cardiac arrest (PARAMEDIC trial) and talking to fellow researchers from the REVIVE cardiac arrest study and discussions with patient and public representatives, we believe the earliest practicable time to contact patients and relatives is once the patient is discharged from ICU and is on a hospital ward. This allows sufficient time
for the research team to be made aware of enrolment, identify who the patient is, check which hospital the patient was transferred to, whether they are still alive and to verify with the hospital team where the patient is within the hospital. Transfer to a ward will indicate that the initial emergency has passed and the patient’s condition will have stabilised. It is also more likely that the patient has regained consciousness and it will avoid any confusion or additional distress of making an approach while the patient remains critically ill in intensive care. A30­1. Will you obtain informed consent from or on behalf of research participants? Yes No
If you will be obtaining consent from adult participants, please give details of who will take consent and how it will be done, with details of any steps to provide information (a written information sheet, videos, or interactive material). Arrangements for adults unable to consent for themselves should be described separately in Part B Section 6, and for children in Part B Section 7.
If you plan to seek informed consent from vulnerable groups, say how you will ensure that consent is voluntary and fully informed.
The Research Paramedics will be fully trained on informed consent and assessing capacity, GCP guidelines, relevant legislation and the trial related procedures around consent. Informed consent will ideally be taken with the patient or their legal representative on the hospital ward, after enrolment into the trial. The Research Paramedic, or hospital team will assess if the patient has capacity to consent. If the patient has capacity, they will be provided with the information sheet explaining the trial and the options for their involvement. The patient will be allowed time to consider the information provided, have the opportunity to ask questions and discuss with others. The Research Paramedic or hospital team will then ask when the patient would like someone to come back to discuss participation further and potentially take consent. In exceptional circumstances if we were not able to make contact with the patient during the hospital stay, we will write
to the patient. If the patient responds to the invitation letter sent by post and agrees to have a home visit, written consent would be taken at the 3 month visit. If you are not obtaining consent, please explain why not.
Please enclose a copy of the information sheet(s) and consent form(s). A30­2. Will you record informed consent (or advice from consultees) in writing? 13
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A30­2. Will you record informed consent (or advice from consultees) in writing? Yes No
A30­3. Why is it not practicable for either the researcher’s organisation, or the current holder of the information required by the researcher, to seek or obtain patient consent for proposed use of patient identifiable information? The occurrence of an out of hospital cardiac arrest is unpredictable. Within seconds of cardiac arrest a person becomes unconscious and thus incapacitated. It will not therefore be possible to obtain prospective consent directly from the research participant. In this setting it will not be practical to consult a carer or independent registered medical practitioner without placing the
potential participant at risk of harm from delaying emergency treatment. A31. How long will you allow potential participants to decide whether or not to take part? As long as they need. A32. Will you recruit any participants who are involved in current research or have recently been involved in any research prior to recruitment? Yes
No
Not Known
If Yes, please give details and justify their inclusion. If Not Known, what steps will you take to find out?
It is unlikely that any participants will already be participating in research studies and paramedics recruiting and treating the patients will have no way of finding out and no time to do this. Participation in research would have no bearing on treatment for out of hosptial cardiac arrest.
A33­1. What arrangements have been made for persons who might not adequately understand verbal explanations or written information given in English, or who have special communication needs?(e.g. translation, use of interpreters) As recruitment will take place in Wales, invitation letters, patient information sheets and consent forms will be translated into Welsh language. We will arrange for back translation to be carried out. Large­print versions of the trial information and questionnaires will be available if needed. A33­2. What arrangements will you make to comply with the principles of the Welsh Language Act in the provision of information to participants in Wales? Invitation letters, patient information sheets and consent forms will be translated into Welsh language. We will arrange for back translation to be carried out. A34. What arrangements will you make to ensure participants receive any information that becomes available during the course of the research that may be relevant to their continued participation? Trial treatment will last for a short period of time so emergence of new information would not affect the treatment of any individual. New research will be monitored by the research team and included in reports to the Data Monitoring Committee who will advise on continuation of the trial if new evidence emerges from other studies. CONFIDENTIALITY In this section, personal data means any data relating to a participant who could potentially be identified. It includes pseudonymised data capable of being linked to a participant through a unique code number. Storage and use of personal data during the study A36. Will you be undertaking any of the following activities at any stage (including in the identification of potential 14
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participants)?(Tick as appropriate) Access to medical records by those outside the direct healthcare team In this section, personal data means any data relating to a participant who could potentially be identified. It includes pseudonymised data capable of being linked to a participant through a unique code number. NHS
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Storage and use of personal data during the study A36. Will you be undertaking any of the following activities at any stage (including in the identification of potential participants)?(Tick as appropriate) Access to medical records by those outside the direct healthcare team Electronic transfer by magnetic or optical media, email or computer networks
Sharing of personal data with other organisations
Export of personal data outside the EEA
Use of personal addresses, postcodes, faxes, emails or telephone numbers
Publication of direct quotations from respondents
Publication of data that might allow identification of individuals
Use of audio/visual recording devices
Storage of personal data on any of the following:
Manual files including X−rays
NHS computers
Home or other personal computers
University computers
Private company computers
Laptop computers
Further details: Access to medical notes is needed to establish mRS at hospital discharge (small group of patients) either the hospital
staff or Research Paramedic will do this. Personal data is needed to WCTU can log surviving patients on HSCIC to track survival to 12 months and also to co­
ordinate the initial contact with patients and to co­ordinate patient follow up visits. Sharing of personal data will include WCTU seeking data from ambulance services hospitals, HSCIC ICNARC and HES as per relevant approvals. A38. How will you ensure the confidentiality of personal data?Please provide a general statement of the policy and procedures for ensuring confidentiality, e.g. anonymisation or pseudonymisation of data. Data will be identified in the study database by unique trial code (TNO) and identificable details will only be used where
this is necessary i.e to contact patients about their enrolment and follow up. If identifiable data are transferred outside the clinical trials unit, secure methods such as encryption are always used in
accordance with the WCTU's standard operating procedures. Published data will be annoymised. A40. Who will have access to participants' personal data during the study? Where access is by individuals outside the direct care team, please justify and say whether consent will be sought. Personal data will be accessed initially by the ambulance services and sent to WCTU for surviving patients (small proportion of patients) so that the WCTU can track survival to 12 months and to co­ordinate contact with patients about their enrolment. Storage and use of data after the end of the study A43. How long will personal data be stored or accessed after the study has ended? Less than 3 months
3 – 6 months
6 – 12 months
12 months – 3 years
Over 3 years
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3 – 6 months
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Over 3 years
INCENTIVES AND PAYMENTS A46. Will research participants receive any payments, reimbursement of expenses or any other benefits or incentives for taking part in this research? Yes No
A47. Will individual researchers receive any personal payment over and above normal salary, or any other benefits or incentives, for taking part in this research? Yes No
A48. Does the Chief Investigator or any other investigator/collaborator have any direct personal involvement (e.g. financial, share holding, personal relationship etc.) in the organisations sponsoring or funding the research that may give rise to a possible conflict of interest? Yes No
NOTIFICATION OF OTHER PROFESSIONALS A49­1. Will you inform the participants’ General Practitioners (and/or any other health or care professional responsible for their care) that they are taking part in the study? Yes No
If Yes, please enclose a copy of the information sheet/letter for the GP/health professional with a version number and date. PUBLICATION AND DISSEMINATION A50. Will the research be registered on a public database? The Department of Health's Research Governance Framework for Health and Social Care and the research governance frameworks for Wales, Scotland and Northern Ireland set out the requirement for registration of trials. Furthermore: Article 19 of the World Medical Association Declaration of Helsinki adopted in 2008 states that “every clinical trial must be registered on a publicly accessible database before recruitment of the first subject”; and the International Committee of Medical Journal Editors (ICMJE) will consider a clinical trial for publication only if it has been registered in an appropriate registry. Please see guidance for more information. Yes No
Please give details, or justify if not registering the research. The trial will be registered with ISCRTN and EudraCT. Please ensure that you have entered registry reference number(s) in question A5­1.
A51. How do you intend to report and disseminate the results of the study?Tick as appropriate: Peer reviewed scientific journals
Internal report
Conference presentation
Publication on website
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Submission to regulatory authorities
Access to raw data and right to publish freely by all investigators in study or by Independent Steering Committee Peer reviewed scientific journals
NHS Internal report
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Publication on website
Other publication
Submission to regulatory authorities
Access to raw data and right to publish freely by all investigators in study or by Independent Steering Committee on behalf of all investigators
No plans to report or disseminate the results
Other (please specify)
A53. Will you inform participants of the results? Yes No
Please give details of how you will inform participants or justify if not doing so. Patients who agree to take part in the follow up will receive a lay summary of the results. 5. Scientific and Statistical Review A54. How has the scientific quality of the research been assessed?Tick as appropriate: Independent external review
Review within a company
Review within a multi−centre research group
Review within the Chief Investigator's institution or host organisation
Review within the research team
Review by educational supervisor Other
Justify and describe the review process and outcome. If the review has been undertaken but not seen by the researcher, give details of the body which has undertaken the review: For all studies except non­doctoral student research, please enclose a copy of any available scientific critique reports, together with any related correspondence. For non­doctoral student research, please enclose a copy of the assessment from your educational supervisor/ institution. A56. How have the statistical aspects of the research been reviewed?Tick as appropriate: Review by independent statistician commissioned by funder or sponsor
Other review by independent statistician
Review by company statistician
Review by a statistician within the Chief Investigator’s institution
Review by a statistician within the research team or multi−centre group
Review by educational supervisor
Other review by individual with relevant statistical expertise
No review necessary as only frequencies and associations will be assessed – details of statistical input not required In all cases please give details below of the individual responsible for reviewing the statistical aspects. If advice has been provided in confidence, give details of the department and institution concerned. Title Forename/Initials Surname
Dr Ranjit
Lall
Department
Warwick Clinical Trials Unit
Institution
University of Warwick
Work Address
Gibbet Hill Road
Coventry Date: 07/03/2014
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Title Forename/Initials Surname
Department
Warwick Clinical Trials Unit
Institution
University of Warwick
Work Address
Gibbet Hill Road
Coventry Reference:
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Post Code
CV4 7AL
Telephone
Fax
Mobile
E­mail
Please enclose a copy of any available comments or reports from a statistician. A57. What is the primary outcome measure for the study? Survival to 30 days post cardiac arrest. A58. What are the secondary outcome measures?(if any) 1.Survived event (sustained ROSC, with spontaneous circulation until admission and transfer of care to medical staff at
the receiving hospital) 2.Survival to hospital discharge (the point at which the patient is discharged from the hospital acute care unit regardless of neurological status, outcome or destination) 3, 6 and 12 months 3.Neurological outcome (modified Rankin Scale (mRS)) at hospital discharge, 3 and 6 months 4.Neurological outcomes (IQCODE and “Two simple questions”) at 3 and 6 months 5.Health related quality of life at 3 and 6 months (SF12 and EQ­5D) 6.Cognitive outcome at 3 months (Mini Mental State Examination (MMSE)) 7.Anxiety and depression at 3 months (Hospital Anxiety and Depression Scale (HADS)) 8.Post Traumatic Stress at 3 months (PTSD civilian checklist (PCL­C)) 9.Hospital length of stay 10.Intensive care length of stay A59. What is the sample size for the research? How many participants/samples/data records do you plan to study in total? If there is more than one group, please give further details below. Total UK sample size:
8000 Total international sample size (including UK): 0 Total in European Economic Area:
0 Further details: 4000 patients will receive adrenaline, 4000 patients will receive placebo. A60. How was the sample size decided upon? If a formal sample size calculation was used, indicate how this was done, giving sufficient information to justify and reproduce the calculation. The target sample size will be 8,000, which is expected to give a width of the 95% CI for the risk ratio of approximately 0.4 or slightly less; for a risk ratio of 1.25 the 95% CI is 1.07 to 1.46, and for risk ratio of 1.0 it is 0.84 to 1.19. There is a
trade­off between precision and practicality in setting a target sample size; above 8,000, there is only a small improvement in precision, but the difficulty and time needed to recruit this number increase significantly. We expect a very small amount of missing data for survival outcomes; in PARAMEDIC we have ascertained survival status for over 99% of randomised patients, and we have therefore not adjusted the sample size estimates to account for missing data. Using a conventional sample size calculation based on a significance test, a sample size of 8,000 would have 93% power to achieve a statistically significant (p<0.05) result if the true treatment difference is a risk ratio of 1.33 (increase from 6% in adrenaline group to 8% in placebo group), or 75% power if the true treatment difference is a risk ratio of 1.25 (increase from 6% to 7.5%). A61. Will participants be allocated to groups at random? Date: 07/03/2014
Yes No
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from 6% in adrenaline group to 8% in placebo group), or 75% power if the true treatment difference is a risk ratio of 1.25 (increase from 6% to 7.5%). NHS
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A61. Will participants be allocated to groups at random? Yes No
If yes, please give details of the intended method of randomisation: Recruitment takes place in an emergency situation therefore telephone or internet randomisation is impractical, the trial will therefore use a system of pre­randomised treatment packs. Trial drugs will be packaged in numbered treatment packs. The pre­randomised sequence will be prepared by the trial statistician. All packs will be identical in appearance; hence clinicians, patients and trial personnel will be unaware of whether any specific pack contains adrenaline or placebo. Treatment packs will be supplied to each ambulance service, in a central location and will be distributed from there to participating ambulance stations and vehicles. When ambulance service personnel identify an
eligible patient, randomisation will be achieved by opening one of the packs carried by the vehicle attending the arrest. A62. Please describe the methods of analysis (statistical or other appropriate methods, e.g. for qualitative research) by which the data will be evaluated to meet the study objectives. The primary analyses will be by intention to treat. 6. MANAGEMENT OF THE RESEARCH A63. Other key investigators/collaborators. Please include all grant co−applicants, protocol co−authors and other key members of the Chief Investigator’s team, including non­doctoral student researchers. Title Forename/Initials Surname
Prof Post
Professor of Emergency Medicine
Qualifications
Employer
University of Warwick
Work Address
Medical School
Gibbet Hill ROad
Post Code
CV4 7AL
Telephone
Fax
Mobile
Work Email
Title Forename/Initials Surname
Post
Patient Representative
Qualifications
Employer
Telephone
Fax
Mobile
Work Email
Title Forename/Initials Surname
Date: 07/03/2014
Post
Qualifications
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Co­Director
, Certificate Mobile
Work Email
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Title Forename/Initials Surname
Prof Post
Co­Director
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Qualifications
Employer
Prehospital, Resuscitation and Emergency Care Research Unit (PRECRU)
Work Address
School of Nursing & Midwifery
Curtin Unviersity
GPO Box U1987 Perth, WA
Post Code
6845 Telephone
Fax
Mobile
Work Email
Title Forename/Initials Surname
Post
Research & Development Lead
Qualifications
Employer
Welsh Ambulance Service
Work Address
Prehospital Emergency Research Unit
Finance Building, Lansdowne Site, Sanatorium Road, Cardiff
Post Code
CF11 8PL
Telephone
Fax
Mobile
Work Email
Title Forename/Initials Surname
Dr Post
Consultant Anaesthetist
Qualifications
Employer
Royal United Hospital Bath NHS Trust
Work Address
Department of Anaesthesia and Intensive Care Medicine
Combe Park
Bath
Post Code
BA1 3NG
Telephone
Fax
Mobile
Work Email
Title Forename/Initials Surname
Dr Post
Head of Clinical Audit & Research Qualifications
Employer
London Ambulance Service NHS Trust
Work Address
Clinical Audit & Research Unit
London Ambulance Service NHS Trust
8­20 Pocock Street, London
Post Code
SE1 8SD
Date: 07/03/2014
Telephone
Fax
20
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NHS
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London Ambulance Service NHS Trust
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London Ambulance Service NHS Trust
8­20 Pocock Street, London
Post Code
SE1 8SD
Clinical Audit & Research Unit
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Mobile
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Title Forename/Initials Surname
Prof Post
Professor of Clinical Practice
Qualifications
Employer
Univeristy of Surrey
Work Address
Duke of Kent Building
University of Surrey
Guildford
Post Code
GU2 7TE
Telephone
Fax
Mobile
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Title Forename/Initials Surname
Prof Post
Professor of Health Economics
Qualifications
Employer
University of Warwick
Work Address
Warwick Clinical Trials Unit
Gibbet Hill Road
Coventry
Post Code
CV4 7AL
Telephone
Fax
Mobile
Work Email
Title Forename/Initials Surname
Prof Post
Qualifications
Employer
University of Warwick
Work Address
Gibbet Hill Road
Coventry
Post Code
CV4 7AL
Telephone
Fax
Mobile
Work Email
Date:
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Post
Title Forename/Initials Surname
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Co­Director of Oxford Clinical Trials Research Unit
Qualifications
Employer
University of Oxford
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Prof Post
Co­Director of Oxford Clinical Trials Research Unit
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University of Oxford
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Associate Professor
Qualifications
Employer
University of Warwick
Work Address
Warwick Medical School
Gibbet Hill Road
Coventry
Post Code
CV4 7AL
Telephone
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Mobile
Work Email
Post
Title Forename/Initials Surname
Medical Director
Qualifications
Employer
North East Ambulance Service NHS Trust
Work Address
Bernicia House, Goldcrest Way
Newburn Riverside
Newcastle Upon Tyne
Post Code
NE15 8NY
Telephone
Fax
Mobile
Work Email
Post
Title Forename/Initials Surname
Divisional Medical Director
Qualifications
Employer
South Central Ambulance Service NHS Trust
Work Address
Post Code
Telephone
Date: 07/03/2014
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Mobile
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Work Address
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Title Forename/Initials Surname
Post
Principal Research Fellow
Qualifications
PhD
Employer
University of Warwick
Work Address
Warwick Clinical Trials Unit
Gibbet Hill Road
Coventry
Post Code
CV4 7AL
Telephone
Fax
Mobile
Work Email
Post
Title Forename/Initials Surname
Co­Director
Qualifications
Employer
Prehospital, Resuscitation and Emergency Care Research Unit (PRECRU) Work Address
School of Nursing & Midwifery
Curtin Unviersity
GPO Box U1987 Perth,
Post Code
6845 Telephone
Fax
Mobile
Work Email
Post
Title Forename/Initials Surname
Medical Director
Qualifications
Employer
West Midlands Ambulance Service NHS Trust
Work Address
Millenium Point
Waterfront Business Park
Waterfront Way, Brierley Hill
Post Code
DY5 1LX
Telephone
Fax
Mobile
Work Email
Post
Title Forename/Initials Surname
Professor of Clinical Trials
Date:
07/03/2014
Qualifications
23
Employer
University of Warwick
Work Address
Warwick Clinical Trials Unit
147538/575440/1/735
Work Email
NHS REC Form
andy.carson@wmas.nhs.uk
Title Forename/Initials Surname
Post
Professor of Clinical Trials
Reference:
14/SC/0157
IRAS Version 3.5
Qualifications
Employer
University of Warwick
Work Address
Warwick Clinical Trials Unit
Gibbet Hill Road
Coventry
Post Code
CV4 7AL
Telephone
Fax
Mobile
Work Email
A64. Details of research sponsor(s) A64­1. Sponsor SP1 Status:
NHS or HSC care organisation Commercial status: Non­Commercial
Academic
Pharmaceutical industry
Medical device industry
Other
If Other, please specify: Contact person Name of organisation University of Warwick
Given name
Family name
Address
Medical School, Gibbet Hill Road
Town/city
Coventry
Post code
CV4 7AL
Country
UNITED KINGDOM
Telephone
Fax
E­mail
wmssponsorship@warwwick.ac.uk
Legal representative in the European Economic Area for the purpose of this trial A legal representative must be appointed for a clinical trial of an investigational medicinal product if the sponsor is not established within the European Economic Area (EEA) (see article 19 of Directive 2001/20/EC). If this applies, please enclose evidence that the legal representative is established within the EEA and has accepted the role of legal representative. Legal Representative
Contact person Name of organisation
Given name
Family name
Date: 07/03/2014
Address
Town/city
24
147538/575440/1/735
Contact person NHS REC Form
Reference:
14/SC/0157
Name of organisation
IRAS Version 3.5
Given name
Family name
Address
Town/city
Post code
Country
Telephone
Fax
E­mail
A65. Has external funding for the research been secured? Funding secured from one or more funders
External funding application to one or more funders in progress
No application for external funding will be made
What type of research project is this? Standalone project
Project that is part of a programme grant
Project that is part of a Centre grant
Project that is part of a fellowship/ personal award/ research training award
Other
Other – please state: Please give details of funding applications. Organisation
The NIHR Evaluation, Trials and Studies Coordinating Centre (NETSCC)
Address
University of Southampton
Alpha House
Enterprise Road, Southampton
Post Code
SO16 7NS
Telephone
02380595586
Fax
Mobile
Email
info@netscc.ac.uk
Funding Application Status: Amount: Secured
In progress
£2,724,486 Duration Years: 4
Months: 6
If applicable, please specify the programme/ funding stream:
What is the funding stream/ programme for this research project?
Date:
07/03/2014
25
147538/575440/1/735
A67. Has this or a similar application been previously rejected by a Research Ethics Committee in the UK or another country? If applicable, please specify the programme/ funding stream:
NHS
REC Form
Reference:
What is the funding stream/ programme for this research project?
14/SC/0157
IRAS Version 3.5
A67. Has this or a similar application been previously rejected by a Research Ethics Committee in the UK or another country? Yes No
Please provide a copy of the unfavourable opinion letter(s). You should explain in your answer to question A6­2 how the reasons for the unfavourable opinion have been addressed in this application. A68­1. Give details of the lead NHS R&D contact for this research: Title Forename/Initials Surname
Organisation
West Midlands (South) Comprehensive Local Research Network
Address
University Hospitals Coventry & Warwickshire NHS Trust Fourth Floor Rotunda (ADA40007) University Hospital, Clifford Bridge Road
Post Code
CV2 2DX
Work Email
Telephone
Fax
Mobile
Details can be obtained from the NHS R&D Forum website: http://www.rdforum.nhs.uk A68­2. Select Comprehensive Local Research Network for this NHS organisation: To support communication between the REC and R&D contacts for this study, please select the Comprehensive Local Research Network (CLRN) for this NHS organisation. This CLRN will be the Lead CLRN for your study. West Midlands (South)
For information about support and advice available through the Lead CLRN and the CLRNs for participating sites see http://www.crncc.nihr.ac.uk/about_us/processes/csp. A map showing the CLRNs is available at http://www.crncc.nihr.ac.uk/about_us/ccrn. A69­1. How long do you expect the study to last in the UK? Planned start date: 01/03/2014
Planned end date: 31/08/2018
Total duration:
Years: 4 Months: 6 Days: A69­2. How long do you expect the study to last in all countries? Planned start date: 01/03/2014
Planned end date: 31/08/2018
Total duration:
Years: 4 Months: 6 Days: Date:
07/03/2014
147538/575440/1/735
26
A70. Definition of the end of trial, and justification in the case where it is not the last visit of the last subject undergoing the trial (1) The trial will end when the last data is entered into the database which could be the last follow up visit or HES data Planned end date: 31/08/2018
Total duration:
NHS REC Form
Reference:
14/SC/0157
Years: 4 Months: 6 Days: IRAS Version 3.5
A70. Definition of the end of trial, and justification in the case where it is not the last visit of the last subject undergoing the trial (1) The trial will end when the last data is entered into the database which could be the last follow up visit or HES data received. A71­2. Where will the research take place? (Tick as appropriate) England
Scotland
Wales
Northern Ireland
Other countries in European Economic Area
Total UK sites in study 87 Does this trial involve countries outside the EU?
Yes No
A72. What host organisations (NHS or other) in the UK will be responsible for the research sites? Please indicate the type of organisation by ticking the box and give approximate numbers of planned research sites: NHS organisations in England
73 NHS organisations in Wales
14 NHS organisations in Scotland
HSC organisations in Northern Ireland
GP practices in England
GP practices in Wales
GP practices in Scotland
GP practices in Northern Ireland
Social care organisations
Phase 1 trial units
Prison establishments
Probation areas
Independent hospitals
Educational establishments
Independent research units
Other (give details)
Acute Trusts will have a single SSI
Total UK sites in study: 87
A75­1. What arrangements will be made to review interim safety and efficacy data from the trial? Will a formal data monitoring committee or equivalent body be convened? The DMC will consist of independent experts with relevant clinical research, and statistical experience. The DMC will monitor the accumulating outcome data, and one of their roles is to recommend cessation of recruitment if a clear result has been reached (i.e. if either adrenaline or placebo is clearly superior). Recruitment will continue during this period. Initial monitoring will be every 3 months. If a formal DMC is to be convened, please forward details of the membership and standard operating procedures to the Research Ethics Committee when available. The REC should also be notified of DMC recommendations and receive summary reports of interim analyses. Date: 07/03/2014
27
A75­2. What are the criteria for electively stopping the trial or other research prematurely? 147538/575440/1/735
We suggest that different thresholds of evidence for early termination are adopted for standard care (adrenaline) or period. Initial monitoring will be every 3 months. NHS REC Form
Reference:
IRAS Version 3.5
If a formal DMC is to be convened, please forward details of the membership and standard operating procedures to the 14/SC/0157
Research Ethics Committee when available. The REC should also be notified of DMC recommendations and receive summary reports of interim analyses. A75­2. What are the criteria for electively stopping the trial or other research prematurely? We suggest that different thresholds of evidence for early termination are adopted for standard care (adrenaline) or placebo being more effective, as it is likely that stronger evidence would be needed to change current standard practice
(adrenaline use) if placebo is found to be superior or if adrenaline is superior the trial wil stop quickly and ambulance services will revert to standard care. We therefore propose that interim analyses are conducted frequently in the early stages of the trial, so that, if adrenaline is superior, this can be detected early. Thus we will minimise any risks to patients while producing robust evidence that will change practice. The outcomes of primary interest for interim analyses are 30 day survival and neurological status. We propose to prepare reports for the DMC initially on a three monthly basis. The exact schedule of interim analyses and the nature of any early stopping rules will be determined by the DMC, in discussion with the investigators, before the start of recruitment. A76. Insurance/ indemnity to meet potential legal liabilities Note: in this question to NHS indemnity schemes include equivalent schemes provided by Health and Social Care (HSC) in Northern Ireland A76­1. What arrangements will be made for insurance and/or indemnity to meet the potential legal liability of the sponsor(s) for harm to participants arising from the management of the research? Please tick box(es) as applicable. Note: Where a NHS organisation has agreed to act as sponsor or co­sponsor, indemnity is provided through NHS schemes. Indicate if this applies (there is no need to provide documentary evidence). For all other sponsors, please describe the arrangements and provide evidence. NHS indemnity scheme will apply (NHS sponsors only)
Other insurance or indemnity arrangements will apply (give details below)
The University has in force a Public and Products Liability policy and a Clinical Trials Insurance Policy which provides cover for claims for “negligent harm” and the activities here are included within that coverage subject to the terms, conditions and exceptions of the policy. Please enclose a copy of relevant documents. A76­2. What arrangements will be made for insurance and/ or indemnity to meet the potential legal liability of the sponsor(s) or employer(s) for harm to participants arising from the design of the research? Please tick box(es) as applicable. Note: Where researchers with substantive NHS employment contracts have designed the research, indemnity is provided through NHS schemes. Indicate if this applies (there is no need to provide documentary evidence). For other protocol authors (e.g. company employees, university members), please describe the arrangements and provide evidence. NHS indemnity scheme will apply (protocol authors with NHS contracts only)
Other insurance or indemnity arrangements will apply (give details below)
The University has in force a Public and Products Liability policy and a Clinical Trials Insurance which provides cover for claims for “negligent harm” and the activities here are included within that coverage subject to the terms, conditions and exceptions of the policy. Please enclose a copy of relevant documents. A76­3. What arrangements will be made for insurance and/ or indemnity to meet the potential legal liability of investigators/collaborators arising from harm to participants in the conduct of the research? Note: Where the participants are NHS patients, indemnity is provided through the NHS schemes or through professional indemnity. Indicate if this applies to the whole study (there is no need to provide documentary evidence). Where non­NHS sites are to be included in the research, including private practices, please describe the arrangements which will be made at these sites and provide evidence. 28
Date: NHS indemnity scheme or professional indemnity will apply (participants recruited at NHS sites only)
07/03/2014
147538/575440/1/735
Research includes non­NHS sites (give details of insurance/ indemnity arrangements for these sites below)
Note: Where the participants are NHS patients, indemnity is provided through the NHS schemes or through professional NHS
REC Form
Reference:
IRAS Version 3.5
indemnity. Indicate if this applies to the whole study (there is no need to provide documentary evidence). Where non­NHS 14/SC/0157
sites are to be included in the research, including private practices, please describe the arrangements which will be made at these sites and provide evidence. NHS indemnity scheme or professional indemnity will apply (participants recruited at NHS sites only)
Research includes non­NHS sites (give details of insurance/ indemnity arrangements for these sites below)
NHS indemnity covers NHS staff, medical academic staff with honorary contracts and those conducting the trial. NHS bodies carry this risk themselves or spread it through the Clinical Negligence Scheme for Trusts, which provides unlimited cover for this risk. Negligent harm cover will be provided by standard NHS arrangements. NHS Indemnity does not give indemnity for compensation in the event of non−negligent harm, so no specific arrangements exist for non−negligent harm for this trial. Please enclose a copy of relevant documents. A77. Has the sponsor(s) made arrangements for payment of compensation in the event of harm to the research participants where no legal liability arises? Yes No
Please enclose a copy of relevant documents. Part B Section 1: Investigational Medicinal Products Information on each IMP. Information on each 'bulk product' before trial­specific operations (blinding, trial specific packaging and labelling) should be provided in this section for each investigational medicinal product (IMP) being tested including each comparator, if applicable. If the trial is performed with several products please create a separate set of the following questions for each product. If the product is a combination product please give separate information for each active substance. Click on the first row and enter details of the product in the following screens. When you have completed the details, click on the navigate button or the "See All" link and return to this section to enter details of the next product. When you have completed details of all products please move to question 13 using the navigation screen. Investigational medicinal products PR1 Adrenaline
13. Indicate which of the following is described below then repeat as necessary for each: This refers to the IMP number: PR1 Investigational medicinal product category: 14. STATUS OF THE IMP If the IMP has a marketing authorisation in the Member State concerned by this application but the trade name and marketing authorisation holder are not fixed in the protocol, go to question 14­.2
14­1. Does the IMP to be used in the trial have a marketing authorisation? Yes
No
Not Answered
14­2. Situations where an IMP to be used in the CT has a MA in the MS concerned, but the protocol allows that any brand of the IMP with a MA in that MS be administered to the trial subjects and it is not possible to clearly identify the IMP(s) in advance of the trial start 29
Date: 07/03/2014
In the protocol, is treatment defined only by active substance? Yes
No
Not Answered
147538/575440/1/735
NHS REC Form
Please enclose a copy of relevant documents. Reference:
14/SC/0157
IRAS Version 3.5
Part B Section 1: Investigational Medicinal Products Information on each IMP. Information on each 'bulk product' before trial­specific operations (blinding, trial specific packaging and labelling) should be provided in this section for each investigational medicinal product (IMP) being tested including each comparator, if applicable. If the trial is performed with several products please create a separate set of the following questions for each product. If the product is a combination product please give separate information for each active substance. Click on the first row and enter details of the product in the following screens. When you have completed the details, click on the navigate button or the "See All" link and return to this section to enter details of the next product. When you have completed details of all products please move to question 13 using the navigation screen. Investigational medicinal products PR1 Adrenaline
13. Indicate which of the following is described below then repeat as necessary for each: This refers to the IMP number: PR1 Investigational medicinal product category: 14. STATUS OF THE IMP If the IMP has a marketing authorisation in the Member State concerned by this application but the trade name and marketing authorisation holder are not fixed in the protocol, go to question 14­.2
14­1. Does the IMP to be used in the trial have a marketing authorisation? Yes
No
Not Answered
14­2. Situations where an IMP to be used in the CT has a MA in the MS concerned, but the protocol allows that any brand of the IMP with a MA in that MS be administered to the trial subjects and it is not possible to clearly identify the IMP(s) in advance of the trial start In the protocol, is treatment defined only by active substance? Yes
No
Not Answered
In the protocol, do treatment regimens allow different combinations of marketed products used according to local clinical practice at some or all investigator sites in the MS? Yes
No
Not Answered
The products to be administered as IMPs are defined as belonging to an ATC group Yes
No
Not Answered
No
Not Answered
Other : Yes
14­3. IMPD submitted: Full IMPD Yes
No
Not Answered
Simplified IMPD Yes
No
Date: 07/03/2014
Not Answered
30
Provide justification for using simplified dossier in the covering letter Summary of product characteristics (SmPC) only 147538/575440/1/735
Full IMPD NHS Yes
REC Form
No
Reference:
14/SC/0157
Not Answered
Simplified IMPD Yes
No
IRAS Version 3.5
Not Answered
Provide justification for using simplified dossier in the covering letter Summary of product characteristics (SmPC) only Yes
No
Not Answered
14­4. Has the use of the IMP been previously authorised in a clinical trial conducted by the sponsor in the Community? Yes
No
Not Answered
14­5. Has the IMP been designated in this indication as an orphan drug in the Community? Yes
No
Not Answered
14­6. Has the IMP been the subject of scientific advice related to this clinical trial? Yes
No
Not Answered
Please indicate source of advice and provide a copy in the CTA request: From the CHMP? Yes
No
Not Answered
CHMP = Committee for Medicinal Products for Human Use
From a MS competent authority? Yes
No
Not Answered
This is a sub­set of questions about each IMP. To return to the list of IMPs select "See all" at the top of the page or select "Navigate". To complete further questions about this IMP select "Next". Description of IMP 15­1. Description of IMP Product name where applicable Adrenaline Product code where applicable ATC codes, if officially registered Pharmaceutical form (use standard terms) Solution for injection in pre­filled syringe
Is this a specific paediatric formulation? Yes
No
Not Answered
Maximum duration of treatment of a subject according to the protocol Dose allowed
First dose for first­in­human clinical trial Specify per day or total: Date:
07/03/2014
Specify total dose (number and unit) Route of administration (relevant to the first dose): per day
31
total
Not Answered
147538/575440/1/735
Dose allowed
NHS
REC Form
First dose for first­in­human clinical trial Reference:
14/SC/0157
Specify per day or total: IRAS Version 3.5
per day
Specify total dose (number and unit) Route of administration (relevant to the first dose): Maximum dose allowed Specify per day or total per day
total
Not Answered
total
Not Answered
Specify total dose (number and unit) mg milligram
(s)
Route of administration (relevant to the maximum dose): Intravenous Use
Routes of administration for this IMP
Intravenous Use This is a sub­set of questions about each IMP. To return to the list of IMPs select "See all" at the top of the page or select "Navigate". To complete further questions about this IMP select "Next". 15­2. Active substances Complete all fields that currently apply to this Active Substance in this Product. If you have IMPs with different concentrations of the Active Substance complete a new Sub­section D for each. Active Substance 1
Name of active substance (INN or Ephinephrine Hydrogentartrate
proposed INN if available): CAS number: 51­42­3
Current sponsor code: Other descriptive name: Adrenaline Tartrate
Full Molecular formula
C13H19NO9
Chemical/biological description of
the Active Substance
Strength
Concentration unit:
mg milligram(s)
Concentration type:
equal
Concentration number (only use both fields for range):
1.82 15­3. Type of IMP Does the IMP contain an active substance: Of chemical origin? Yes
No
Not Answered
Of biological / biotechnological origin?(other than Advanced Therapy IMP (ATIMP)) Yes
No
Not Answered
Yes
No
Not Answered
No
Not Answered
Is this a:
Advanced Therapy IMP (ATIMP) (1) Combination product that includes a device, but does not involve an Advanced Therapy Date: 07/03/2014
Yes
32
147538/575440/1/735
Radiopharmaceutical medicinal product? Yes
No
Not Answered
Immunological medicinal product (e.g. vaccine, allergen, immune serum)? Yes
No
Not Answered
Of biological / biotechnological origin?(other than Advanced Therapy IMP (ATIMP)) Yes
No
Yes
No
Not Answered
Combination product that includes a device, but does not involve an Advanced Therapy Yes
No
Not Answered
Radiopharmaceutical medicinal product? Yes
No
Not Answered
Immunological medicinal product (e.g. vaccine, allergen, immune serum)? Yes
No
Not Answered
Plasma derived medicinal product? Yes
No
Not Answered
Extractive medicinal product? Yes
No
Not Answered
Recombinant medicinal product? Yes
No
Not Answered
Medicinal product containing genetically modified organisms? Yes
No
Not Answered
Herbal medicinal product? Yes
No
Not Answered
Homeopathic medicinal product? Yes
No
Not Answered
Another type of medicinal product? Yes
No
Not Answered
Yes
No
Not Answered
Is this a:
NHS REC Form
(1) Advanced Therapy IMP (ATIMP)
Reference:
14/SC/0157
Not Answered
IRAS Version 3.5
Specify the mode of action for the active substance in this medicinal product The mode of action should briefly describe the chemical, biochemical, immunological or biological means that the IMP uses to effect its pharmaceutical action. Adrenaline is a direct acting sympathomimetic agent.
Is it an IMP to be used in a first­in­human clinical trial? (1,2,3,4,5)Complete sections D.4, D.5, D.6. and D.7, as applicable (2,3)
As defined in Annex 1 part IV of Directive 2001/83/EC as amended (4) As defined in Article 2(1)(b) of Regulation 1394/2007/EC (6)
Guideline on strategies to identify and mitigate risks for first­in­human clinical trials with investigational medicinal products. EMEA/CHMP/SWP/28367/2007 Information on Placebo
13. Is a there a placebo: Yes No
PL1
Pharmaceutical form:
Solution for injection in pre­filled syringe
Route of administration:
Intravenous Use
Which IMP is it a placebo for? Specify IMP Number(s) from IMPs list IMP 1
PR1
Composition, apart from the active substance(s):
Is it otherwise identical to the IMP?
Yes No
Part B: Section 6 ­ Adults unable to consent for themselves
A. Clinical trials of investigational medicinal products Date: 07/03/2014
33
In this sub­section, an adult means a person aged 16 or over. 147538/575440/1/735
(6)
Guideline on strategies to identify and mitigate risks for first­in­human clinical trials with investigational medicinal products. EMEA/CHMP/SWP/28367/2007 NHS REC Form
Reference:
14/SC/0157
IRAS Version 3.5
Information on Placebo
13. Is a there a placebo: Yes No
PL1
Pharmaceutical form:
Solution for injection in pre­filled syringe
Route of administration:
Intravenous Use
Which IMP is it a placebo for? Specify IMP Number(s) from IMPs list IMP 1
PR1
Composition, apart from the active substance(s):
Is it otherwise identical to the IMP?
Yes No
Part B: Section 6 ­ Adults unable to consent for themselves
A. Clinical trials of investigational medicinal products In this sub­section, an adult means a person aged 16 or over. A1. What clinical condition(s) will the participants have? The trial must relate directly to this condition. Out of Hospital Cardiac Arrest A2. Could the trial be carried out equally effectively if confined to adults capable of giving consent? Yes No
A3. Who in the research team will decide whether or not the participants have the capacity to give consent? What training/experience will they have to enable them to reach this decision? The Research Paramedics will be fully trained on informed consent and assessing capacity, GCP guidelines, relevant legislation and the trial related procedures around consent. A4. What benefit is the administration of the investigational medicinal product expected to produce for these participants? You may refer back to your answer to Question A24. There is the potential amongst patients who receive adrenaline that a greater number will have their hearts re­started and will survive in the short term (mins to hours). The available evidence on long­term survival (survival to hospital discharge) suggests that some participants who are randomised to placebo will survive to leave hospital when they would have died if they had received adrenaline; that is they will survive as a result of participating in the trial. Participants receiving placebo may also avoid the potential side effects of adrenaline (irregular heart beat, adverse effects on metabolics, brain injury). Participation in the study will provide critical information about the most effective way to resuscitate future patients that sustain an out of hospital cardiac arrest. A5. Will the trial involve any foreseeable risk or burden for these participants, or interfere in any way with their freedom of action or privacy? 34
Date:
07/03/2014
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Yes No
Is it otherwise identical to the IMP?
Yes NHS REC Form
No
Reference:
14/SC/0157
IRAS Version 3.5
Part B: Section 6 ­ Adults unable to consent for themselves
A. Clinical trials of investigational medicinal products In this sub­section, an adult means a person aged 16 or over. A1. What clinical condition(s) will the participants have? The trial must relate directly to this condition. Out of Hospital Cardiac Arrest A2. Could the trial be carried out equally effectively if confined to adults capable of giving consent? Yes No
A3. Who in the research team will decide whether or not the participants have the capacity to give consent? What training/experience will they have to enable them to reach this decision? The Research Paramedics will be fully trained on informed consent and assessing capacity, GCP guidelines, relevant legislation and the trial related procedures around consent. A4. What benefit is the administration of the investigational medicinal product expected to produce for these participants? You may refer back to your answer to Question A24. There is the potential amongst patients who receive adrenaline that a greater number will have their hearts re­started and will survive in the short term (mins to hours). The available evidence on long­term survival (survival to hospital discharge) suggests that some participants who are randomised to placebo will survive to leave hospital when they would have died if they had received adrenaline; that is they will survive as a result of participating in the trial. Participants receiving placebo may also avoid the potential side effects of adrenaline (irregular heart beat, adverse effects on metabolics, brain injury). Participation in the study will provide critical information about the most effective way to resuscitate future patients that sustain an out of hospital cardiac arrest. A5. Will the trial involve any foreseeable risk or burden for these participants, or interfere in any way with their freedom of action or privacy? Yes No
If Yes, please give an assessment below. You may refer back to your answers to Questions A22 and A23. Highlight any risk, burden or discomfort specific to these participants. Justify in relation to the potential benefits.
Risks and burdens: A fundamental issue in this trial is the question of whether the current evidence on the use of adrenaline in cardiac arrest raises sufficient doubt about its efficacy and concern about its potential harm to justify a trial that involves withholding adrenaline from some participants. Most clinical drug trials involve either the comparison of a new drug with the current best treatment or in cases where no current best treatment exists, with a placebo. This trial is unusual in that the underlying hypothesis is that current best practice may be harmful therefore it is ethically necessary to seek evidence to confirm or refute this hypothesis, and that this evidence can only reliably be obtained by a trial that includes participants who do not receive currently recommended treatment. The aim is not to investigate whether another drug is better than adrenaline but to investigate whether adrenaline is more harmful than no adrenaline. The hypothesis that adrenaline is harmful raises the question of what is meant by harm. As we have outlined in our review of current evidence, there is evidence that adrenaline as currently used improves the rate of return of spontaneous circulation (ROSC). Thus it is possible that some people who are entered into the trial and are randomised to receive placebo may fail to achieve return of spontaneous circulation as a result of participating in the trial. However the available evidence on long­term survival (survival to hospital discharge) suggests that some participants who are randomised to placebo will survive to leave hospital when they would have died if they had received adrenaline; that is they will survive as a result of participating in the trial. So for individual participants there is a risk/benefit trade­off for participation which is uncertain because we cannot know on an individual patient basis which person will benefit from the adrenaline and who will be harmed by it. The current evidence suggests that more people will be harmed than will benefit (if we consider survival to discharge
more beneficial than initial survival followed by early death). However the evidence is not so strong that we can say 35
Date: 07/03/2014
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adrenaline should not be used. As we have shown in our survey of practitioners there is equipoise on this question. Given the uncertainty of the evidence, and the life threatening nature of the condition being treated, it is ethically important that we obtain the best evidence we can to justify treatment, while ensuring that the interests of the received adrenaline; that is they will survive as a result of participating in the trial. So for individual participants there is a risk/benefit trade­off for participation which is uncertain because we cannot know on an individual patient basis NHS
REC Form
Reference:
IRAS Version 3.5
which person will benefit from the adrenaline and who will be harmed by it. 14/SC/0157
The current evidence suggests that more people will be harmed than will benefit (if we consider survival to discharge
more beneficial than initial survival followed by early death). However the evidence is not so strong that we can say adrenaline should not be used. As we have shown in our survey of practitioners there is equipoise on this question. Given the uncertainty of the evidence, and the life threatening nature of the condition being treated, it is ethically important that we obtain the best evidence we can to justify treatment, while ensuring that the interests of the research participants remain paramount. In considering the interests of the research participants the question is whether for any individual participant the benefits of participating outweigh the risk of harm, or at least the harm/benefit balance is neutral. Based on current evidence it would seem that risks and benefits from participating in this trial are reasonably balanced (if a participant is randomised to placebo they may have a reduced chance of immediate survival but an increased chance of surviving to leave hospital. Our initial PPI work suggest that members
of the public weigh long term survival higher than short term recovery of spontaneous circulation so it would seem reasonable to assume potential participants might agree to taking part if they were able to do so. Minimising risk The study will be overseen by a Trial Steering Committee (TSC) and Data Monitoring Committee (DMC) appointed by the National Institute for Health Research Health Technology Assessment Programme Director. The majority of members of the TSC will be independent from the study investigators. All members of the DMC will be independent.
The study Chief Investigators and other members of the study team may attend meetings in an advisory capacity at the request of the DMC chair. The role of the TSC is to provide overall supervision for a trial on behalf of the Trial Sponsor and Trial Funder and to ensure that the trial is conducted to the rigorous standards set out in the Department of Health’s Research Governance Framework for Health and Social Care and the Guidelines for Good Clinical Practice. The Data Monitoring Committee (DMC) will monitor safety in this trial. The outcomes of primary interest are long­term
outcomes (30 day survival and neurological status). We will regularly prepare reports for the DMC initially at an interval to be confirmed by that group. The DMC will determine the nature of any early stopping rules. We suggest a
differing threshold is adopted for early termination if standard care (adrenaline) is more effective compared to if placebo is more effective. This is based on a combination of minimising any risks to patients whilst producing robust evidence that will change practice. We suggest that the balance of evidence that would be needed to change current standard practice (adrenaline use) to be greater. Patient and public involvement. Because of the particular ethical difficulty of conducting a trial which involves withholding a standard treatment, and the major life changing impact on participants, it will be imperative to have procedures for close surveillance of trial data. To address these concerns we will include two PPI representatives in the Trial Steering Committee. A6. What arrangements will be made to identify and seek informed consent from a legal representative? In this setting it will not be practical to consult a carer or independent registered medical practitioner without placing the
potential participant at risk of harm from delaying emergency treatment. We consider it unlikely that even if it were possible to seek consent from a personal legal representative, that in light of the emotional distress of the cardiac arrest will cause, that any such person would be likely to have the capacity to make an informed decision in the limited time available. A7. Is it possible that a participant requiring urgent treatment might need to be recruited into the trial before it is possible to identify and seek consent from a legal representative? Yes No
If Yes, outline how decisions will be made on the inclusion of participants and what arrangements will be made to seek consent from the participant (if capacity has been recovered) or a legal representative as soon as practicable thereafter.
The clinical trial relates directly to the treatment of cardiac arrest, which is a life­threatening emergency. All patients that suffer a cardiac arrest will lack capacity. There are no alternative groups of patients amongst whom this research could be conducted. All patients will lack capacity throughout the intervention period of the trial due to the nature of the underlying medical condition (cardiac arrest). The occurrence of an out of hospital cardiac arrest is unpredictable. Within seconds of cardiac arrest a person becomes unconscious and thus incapacitated. It will not therefore be possible to obtain prospective consent directly from the research participant. 07/03/2014
36
Date:
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Treatment (in the form of CPR) must be started immediately in an attempt to save the person’s life. Delay in the initiation of CPR and other emergency treatment (e.g. defibrillation) is associated with worse outcomes. Observational studies suggest that if adrenaline is effective, the earlier it is given the more likely it will be beneficial. All patients will lack capacity throughout the intervention period of the trial due to the nature of the underlying medical condition (cardiac arrest). NHS
REC Form
Reference:
IRAS Version 3.5
14/SC/0157
The occurrence of an out of hospital cardiac arrest is unpredictable. Within seconds of cardiac arrest a person becomes unconscious and thus incapacitated. It will not therefore be possible to obtain prospective consent directly from the research participant. Treatment (in the form of CPR) must be started immediately in an attempt to save the person’s life. Delay in the initiation of CPR and other emergency treatment (e.g. defibrillation) is associated with worse outcomes. Observational studies suggest that if adrenaline is effective, the earlier it is given the more likely it will be beneficial. In this setting it will not be practical to consult a carer or independent registered medical practitioner without placing the potential participant at risk of harm from delaying emergency treatment. We consider it unlikely that even if it were possible to seek consent from a personal legal representative, that in light of the emotional distress of the cardiac arrest will cause, that any such person would be likely to have the capacity to make an informed decision in the limited time available. A8. What arrangements will be made to continue to consult legal representatives during the course of the research where necessary? For surviving patients, in the event that a patient lacks capacity to consent to continue to take part in the study, the Research Paramedic will work with the hospital team to identify a legal representative. The legal representative will be approached and be provided with the information sheet explaining the trial and the options for theirs and the patient’s involvement, including the need for them to give consent on behalf of the patient and
complete questionnaires on behalf of the patient. The legal representative will then have time to consider the information provided. The Research Paramedic or hospital team will then ask when the legal representative would like someone to come back to discuss participation further and potentially take consent. The legal representative may decide it is not an appropriate time to discuss the trial or they may decide that the patient would not want to take part in which case their feelings will be respected and their decision about taking part will be recorded. It is possible that the patient will have regained capacity by the time the 3 month visit is due. When contacting the legal representative to arrange the 3 month visit, we will ask if we can speak with the patient. If on assessment of the patient either on the phone or on the visit it is found that the patient still lacks capacity the legal representative will be asked to complete the questionnaires on behalf of the patient. If the patient has capacity then information will be provided about the trial and consent sought. A9. Will steps be taken to provide information about the trial to participants, according to their capacity of understanding, and to consider the wishes of participants capable of forming an opinion? Yes No
If Yes, give details.
The first attempt to contact the patient and inform them of their enrolment into the trial will be during their stay in hospital before hospital discharge. We plan to make contact as soon as practically possible after the initial emergency has passed and taking the utmost care and sensitivity in doing so. Following our experience from a 4,400 patient study in out of hospital cardiac arrest (PARAMEDIC trial) and talking to fellow researchers from the REVIVE cardiac arrest study and discussions with patient and public representatives, we believe the earliest practicable time to contact patients and relatives is once the patient is discharged from ICU and is on a hospital ward by which time initial emergency will have passed. This allows sufficient time for the research team to be made
aware of enrolment, identify who the patient is, check which hospital the patient was transferred to, whether they are still alive and to verify with the hospital team where the patient is within the hospital. Transfer to a ward will indicate that the initial emergency has passed and the patient’s condition will have stabilised. It is also more likely that the patient has regained consciousness and it will avoid any confusion or additional distress of making an approach while the patient remains critically ill in intensive care. Procedure The Research Paramedic, or hospital team will assess if the patient has capacity to consent. If the patient has capacity, they will be provided with the information sheet explaining the trial and the options for their involvement. The patient will be allowed time to consider the information provided, have the opportunity to ask questions and discuss with others. The Research Paramedic or hospital team will then ask when the patient would like someone to come back to discuss participation further and potentially take consent. The patient may decide it is not an appropriate time to discuss the trial or they may decide that they do not want to be involved in which case their feelings will be respected and their decision about continuing in the trial will be recorded. We anticipate this will be a very small group of patients per month per hospital. A10­1. What will be the criteria for withdrawal of participants? 37
Date:
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A patient or their legal representative can withdraw from the trial at any point. If a patient declines to take part in the follow up visits we will check that they are happy for us to continue to collect data on their stay in hospital and recovery to 12 months. We anticipate this will be a very small group of patients per month per hospital. NHS REC Form
Reference:
14/SC/0157
IRAS Version 3.5
A10­1. What will be the criteria for withdrawal of participants? A patient or their legal representative can withdraw from the trial at any point. If a patient declines to take part in the follow up visits we will check that they are happy for us to continue to collect data on their stay in hospital and recovery to 12 months. A10­2. Where a participant is recruited prior to consent being obtained, and consent is later withheld or the participant dies before consent can be given, what provisions will apply to the study data collected up to this point? In the event that a patient dies prior to obtaining consent from them or their legal representative, we will continue to use
the study data collected up until that point. At the point of seeking consent from the patient or their legal representative the study intervention will have ceased and the patient will be during a period of follow­up. We will therefore seek consent to continue in the follow­up phase of the
trial. In the event that a participant declines follow­up we will establish whether they agree to us to continue to collect information about their health from information sources such as their medical records and the Health and Social Care Information Centre. In the event that the patient declines both the face to face and remote follow­up they will be withdrawn from further data collection. Based on our experience in previous trials it is exceptionally rare that a patient or legal representative will request withdrawal of study data already collected. Post randomisation exclusions run the risk of introducing significant bias which would be likely to damage the validity of the findings of this research. In the event of such a request we would remove all identifiable information relating to that subject but it is our intention to include the baseline and primary outcome data for all patients in the study. Any requests to withdraw all data already collected will be assessed by the Data Monitoring Committee who will provide an opinion about the consequences of the withdrawal of that data to the Research Ethics Committee on a case by case basis. Part B: Section 8 ­ Additional information for applications to National Information Governance Board for Health and Social Care Responses to frequently asked questions on NIGB applications are available at http://www.nigb.nhs.uk/ecc/eccfrequently
1. Do you plan to extract data from Hospital Episode Statistics (HES) or the Secondary Uses Service (SUS)? Yes No
16. Do you have anything to add in support of the application, which is not included elsewhere on the form? PART C: Overview of research sites Please enter details of the host organisations (Local Authority, NHS or other) in the UK that will be responsible for the research sites. For NHS sites, the host organisation is the Trust or Health Board. Where the research site is a primary care site, e.g. GP practice, please insert the host organisation (PCT or Health Board) in the Institution row and insert the research site (e.g. GP practice) in the Department row. Investigator Research site identifier IN1
Investigator Name NHS site
Forename
Non­NHS site
Andy
Middle name
Family name
Carson
Country: England
Email
andy.carson@wmas.nhs.uk
Qualification (MD...)
BSc, MB ChB, RCCP, RCGP
Country
UNITED KINGDOM
Date: 07/03/2014
Organisation name
Address
38
WEST MIDLANDS AMBULANCE SERVICE NHS TRUST
WATERFRONT BUSINESS 147538/575440/1/735
Research Ethics Committee on a case by case basis. NHS
REC Form
Reference:
IRAS Version 3.5
14/SC/0157
Part B: Section 8 ­ Additional information for applications to National Information Governance Board for Health and Social Care Responses to frequently asked questions on NIGB applications are available at http://www.nigb.nhs.uk/ecc/eccfrequently
1. Do you plan to extract data from Hospital Episode Statistics (HES) or the Secondary Uses Service (SUS)? Yes No
16. Do you have anything to add in support of the application, which is not included elsewhere on the form? PART C: Overview of research sites Please enter details of the host organisations (Local Authority, NHS or other) in the UK that will be responsible for the research sites. For NHS sites, the host organisation is the Trust or Health Board. Where the research site is a primary care site, e.g. GP practice, please insert the host organisation (PCT or Health Board) in the Institution row and insert the research site (e.g. GP practice) in the Department row. Investigator Research site identifier IN1
Investigator Name NHS site
Forename
Non­NHS site
Andy
Middle name
Family name
Carson
Country: England
Email
andy.carson@wmas.nhs.uk
Qualification (MD...)
BSc, MB ChB, RCCP, RCGP
Country
UNITED KINGDOM
Organisation name
WEST MIDLANDS AMBULANCE SERVICE NHS TRUST
Address
WATERFRONT BUSINESS PARK
WATERFRONT WAY
BRIERLEY HILL WEST MIDLANDS
Post Code
DY5 1LX
IN2
NHS site
Forename
Non­NHS site
Kyee
Middle name
Family name
Han
Country: England
Email
kyee.han@neas.uk
Qualification (MD...)
MBBS, FRCS, FFAEM, FCEM
Country
UNITED KINGDOM
Organisation name
NORTH EAST AMBULANCE SERVICE NHS TRUST
Address
BENICIA HOUSE
GOLDCREST WAY
NEWBURN RIVERSIDE NEWCASTLE UPON TYNE TYNE
AND WEAR
Date: 07/03/2014
Post Code
NE15 8NY
39
147538/575440/1/735
16. Do you have anything to add in support of the application, which is not included elsewhere on the form? NHS REC Form
Reference:
14/SC/0157
IRAS Version 3.5
PART C: Overview of research sites Please enter details of the host organisations (Local Authority, NHS or other) in the UK that will be responsible for the research sites. For NHS sites, the host organisation is the Trust or Health Board. Where the research site is a primary care site, e.g. GP practice, please insert the host organisation (PCT or Health Board) in the Institution row and insert the research site (e.g. GP practice) in the Department row. Investigator Research site identifier IN1
Investigator Name NHS site
Forename
Non­NHS site
Middle name
Family name
Country: England
Email
Qualification (MD...)
Organisation name
WEST MIDLANDS AMBULANCE SERVICE NHS TRUST
Address
WATERFRONT BUSINESS PARK
WATERFRONT WAY
BRIERLEY HILL WEST MIDLANDS
Post Code
DY5 1LX
Country
UNITED KINGDOM
IN2
NHS site
Forename
Non­NHS site
Middle name
Family name
Country: England
Email
Qualification (MD...)
Organisation name
NORTH EAST AMBULANCE SERVICE NHS TRUST
Address
BENICIA HOUSE
GOLDCREST WAY
NEWBURN RIVERSIDE NEWCASTLE UPON TYNE TYNE
AND WEAR
Post Code
NE15 8NY
Country
UNITED KINGDOM
IN3
NHS site
Forename
Non­NHS site
Middle name
Family name
Country: England
Email
Qualification (MD...)
Date: 07/03/2014
40
Organisation name
SOUTH CENTRAL AMBULANCE SERV NHS TRUST
Address
SOUTHERN HOUSE
Country
147538/575440/1/735
UNITED KINGDOM
Non­NHS site
Middle name
NHS REC Form Reference:
14/SC/0157
Country: England
Organisation name
SOUTH CENTRAL AMBULANCE SERV NHS TRUST
Address
SOUTHERN HOUSE
SPARROWGROVE, OTTERBOURNE
WINCHESTER Post Code
SO21 2RU
IRAS Version 3.5
Family name
Email
Qualification (MD...)
Country
UNITED KINGDOM
IN4
NHS site
Forename
Non­NHS site
Middle name
Family name
Country: Wales
Email
Institution name
Welsh Ambulance Service
Qualification (MD...)
Country
UNITED KINGDOM
Department name
IN5
Street address
Prehospital Emergency Research Unit
Town/city
Finance Building, Lansdowne Site, Post Code
CF11 8PL
NHS site
Forename
Non­NHS site
Middle name
Family name
Country: England
Email
Qualification (MD...)
Organisation name
LONDON AMBULANCE SERVICE NHS TRUST
Country
Address
220 WATERLOO ROAD
@lond­
amb.nhs.uk
UNITED KINGDOM
LONDON GREATER LONDON
Post Code
SE1 8SD
IN24
NHS site
Forename
Non­NHS site
Middle name
Family name
Country: England
Email
Organisation name
Address
Date: 07/03/2014
UNIVERSITY HOSPITALS COVENTRY AND WARWICKSHIRE NHS TRUST
WALSGRAVE GENERAL 41
HOSPITAL
CLIFFORD BRIDGE ROAD
COVENTRY WEST MIDLANDS
Qualification (MD...)
Country
147538/575440/1/735
Email
Country: England
NHS REC Form
Reference:
14/SC/0157
Organisation name
UNIVERSITY HOSPITALS COVENTRY AND WARWICKSHIRE NHS TRUST
Address
WALSGRAVE GENERAL HOSPITAL
CLIFFORD BRIDGE ROAD
COVENTRY WEST MIDLANDS
Post Code
CV2 2DX
IRAS Version 3.5
Qualification (MD...)
Country
PART D: Declarations
D1. Declaration by Chief Investigator 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
The information in this form is accurate to the best of my knowledge and belief and I take full responsibility for it.
I undertake to abide by the ethical principles underlying the Declaration of Helsinki and good practice guidelines on the proper conduct of research. If the research is approved I undertake to adhere to the study protocol, the terms of the full application as approved and any conditions set out by review bodies in giving approval. I undertake to notify review bodies of substantial amendments to the protocol or the terms of the approved application, and to seek a favourable opinion from the main REC before implementing the amendment. I undertake to submit annual progress reports setting out the progress of the research, as required by review bodies. I am aware of my responsibility to be up to date and comply with the requirements of the law and relevant guidelines relating to security and confidentiality of patient or other personal data, including the need to register when necessary with the appropriate Data Protection Officer. I understand that I am not permitted to disclose identifiable data to third parties unless the disclosure has the consent of the data subject or, in the case of patient data in England and Wales, the disclosure is covered by the terms of an approval under Section 251 of the NHS Act 2006. I understand that research records/data may be subject to inspection by review bodies for audit purposes if required. I understand that any personal data in this application will be held by review bodies and their operational managers and that this will be managed according to the principles established in the Data Protection Act 1998. I understand that the information contained in this application, any supporting documentation and all correspondence with review bodies or their operational managers relating to the application: l Will be held by the REC (where applicable) until at least 3 years after the end of the study; and by NHS R&D offices (where the research requires NHS management permission) in accordance with the NHS Code of Practice on Records Management. l May be disclosed to the operational managers of review bodies, or the appointing authority for the REC (where applicable), in order to check that the application has been processed correctly or to investigate any complaint. l May be seen by auditors appointed to undertake accreditation of RECs (where applicable). l Will be subject to the provisions of the Freedom of Information Acts and may be disclosed in response to requests made under the Acts except where statutory exemptions apply. l May be sent by email to REC members. I understand that information relating to this research, including the contact details on this application, may be held on national research information systems, and that this will be managed according to the principles established in the Data Protection Act 1998. 42
Date:
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11.07/03/2014
I understand that the main REC or its operational managers may share information in this application or supporting documentation with the Medicines and Healthcare products Regulatory Agency (MHRA) where it is relevant to the Agency’s statutory responsibilities. NHS REC Form Reference:
14/SC/0157
IRAS Version 3.5
PART D: Declarations
D1. Declaration by Chief Investigator 1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
The information in this form is accurate to the best of my knowledge and belief and I take full responsibility for it.
I undertake to abide by the ethical principles underlying the Declaration of Helsinki and good practice guidelines on the proper conduct of research. If the research is approved I undertake to adhere to the study protocol, the terms of the full application as approved and any conditions set out by review bodies in giving approval. I undertake to notify review bodies of substantial amendments to the protocol or the terms of the approved application, and to seek a favourable opinion from the main REC before implementing the amendment. I undertake to submit annual progress reports setting out the progress of the research, as required by review bodies. I am aware of my responsibility to be up to date and comply with the requirements of the law and relevant guidelines relating to security and confidentiality of patient or other personal data, including the need to register when necessary with the appropriate Data Protection Officer. I understand that I am not permitted to disclose identifiable data to third parties unless the disclosure has the consent of the data subject or, in the case of patient data in England and Wales, the disclosure is covered by the terms of an approval under Section 251 of the NHS Act 2006. I understand that research records/data may be subject to inspection by review bodies for audit purposes if required. I understand that any personal data in this application will be held by review bodies and their operational managers and that this will be managed according to the principles established in the Data Protection Act 1998. I understand that the information contained in this application, any supporting documentation and all correspondence with review bodies or their operational managers relating to the application: l Will be held by the REC (where applicable) until at least 3 years after the end of the study; and by NHS R&D offices (where the research requires NHS management permission) in accordance with the NHS Code of Practice on Records Management. l May be disclosed to the operational managers of review bodies, or the appointing authority for the REC (where applicable), in order to check that the application has been processed correctly or to investigate any complaint. l May be seen by auditors appointed to undertake accreditation of RECs (where applicable). l Will be subject to the provisions of the Freedom of Information Acts and may be disclosed in response to requests made under the Acts except where statutory exemptions apply. l May be sent by email to REC members. I understand that information relating to this research, including the contact details on this application, may be held on national research information systems, and that this will be managed according to the principles established in the Data Protection Act 1998. I understand that the main REC or its operational managers may share information in this application or supporting documentation with the Medicines and Healthcare products Regulatory Agency (MHRA) where it is relevant to the Agency’s statutory responsibilities. Where the research is reviewed by a REC within the UK Health Departments Research Ethics Service, I understand that the summary of this study will be published on the website of the National Research Ethics Service (NRES), together with the contact point for enquiries named below. Publication will take place no earlier
than 3 months after issue of the ethics committee’s final opinion or the withdrawal of the application. Contact point for publication(Not applicable for R&D Forms)
NRES would like to include a contact point with the published summary of the study for those wishing to seek further information. We would be grateful if you would indicate one of the contact points below.
Date: Chief Investigator
07/03/2014
Sponsor
Study co­ordinator
43
147538/575440/1/735
NHS
REC Form
Reference:
Contact point for publication(Not applicable for R&D Forms)
14/SC/0157
IRAS Version 3.5
NRES would like to include a contact point with the published summary of the study for those wishing to seek further information. We would be grateful if you would indicate one of the contact points below.
Chief Investigator
Sponsor
Study co­ordinator
Student
Other – please give details
None
Access to application for training purposes (Not applicable for R&D Forms)
Optional – please tick as appropriate: I would be content for members of other RECs to have access to the information in the application in confidence for training purposes. All personal identifiers and references to sponsors, funders and research units would be removed. This section was signed electronically by Prof Gavin Perkins on 06/03/2014 09:03. Job Title/Post:
Professor
Organisation:
University of Warwick
Email:
Signature: ..................................................... Print Name: Date: (dd/mm/yyyy)
D2. Declaration by the sponsor's representative If there is more than one sponsor, this declaration should be signed on behalf of the co−sponsors by a representative of the lead sponsor named at A64­1.
I confirm that: 1.
This research proposal has been discussed with the Chief Investigator and agreement in principle to sponsor the research is in place. 2. An appropriate process of scientific critique has demonstrated that this research proposal is worthwhile and of
high scientific quality. 3. Any necessary indemnity or insurance arrangements, as described in question A76, will be in place before this research starts. Insurance or indemnity policies will be renewed for the duration of the study where necessary. 4. Arrangements will be in place before the study starts for the research team to access resources and support to deliver the research as proposed. 5. Arrangements to allocate responsibilities for the management, monitoring and reporting of the research will be in place before the research starts. 6. The duties of sponsors set out in the Research Governance Framework for Health and Social Care will be undertaken in relation to this research. 7. The statutory responsibilities of sponsors set out in the Medicines for Human Use (Clinical Trials) Regulations 2004 will be undertaken in relation to this trial. Date: 07/03/2014
147538/575440/1/735
44
8. Where the research is reviewed by a REC within the UK Health Departments Research Ethics Service, I understand that the summary of this study will be published on the website of the National Research Ethics Service (NRES), together with the contact point for enquiries named in this application. Publication will take Date: NHS
REC Form
(dd/mm/yyyy)
Reference:
14/SC/0157
IRAS Version 3.5
D2. Declaration by the sponsor's representative If there is more than one sponsor, this declaration should be signed on behalf of the co−sponsors by a representative of the lead sponsor named at A64­1.
I confirm that: 1.
2.
This research proposal has been discussed with the Chief Investigator and agreement in principle to sponsor the research is in place. An appropriate process of scientific critique has demonstrated that this research proposal is worthwhile and of
high scientific quality. Any necessary indemnity or insurance arrangements, as described in question A76, will be in place before this research starts. Insurance or indemnity policies will be renewed for the duration of the study where necessary. Arrangements will be in place before the study starts for the research team to access resources and support to deliver the research as proposed. Arrangements to allocate responsibilities for the management, monitoring and reporting of the research will be in place before the research starts. The duties of sponsors set out in the Research Governance Framework for Health and Social Care will be undertaken in relation to this research. The statutory responsibilities of sponsors set out in the Medicines for Human Use (Clinical Trials) Regulations 2004 will be undertaken in relation to this trial. Where the research is reviewed by a REC within the UK Health Departments Research Ethics Service, I understand that the summary of this study will be published on the website of the National Research Ethics Service (NRES), together with the contact point for enquiries named in this application. Publication will take place no earlier than 3 months after issue of the ethics committee's final opinion or the withdrawal of the application. 3.
4.
5.
6.
7.
8.
This section was signed electronically by Mrs Jane Prewett on 06/03/2014 09:52. Job Title/Post:
Deputy Director, RSS
Organisation:
University of Warwick
Email:
Date: 07/03/2014
45
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